Gnomad V4.1.1 Update Missing Constraint Metrics from V4.1.0

Hi!

We’re working on a project using the constraint metrics (specifically missense and synonymous o/e) provided by Gnomad. However, we recently noticed that the constraint tables displayed in V4.1.0 are no longer available in V4.1.1 for some genes, such as GJA3. I was wondering why this is the case.

Is the missing constraint related to the changes in LOEUF calculation? Since we are only interested in missense and synonymous, can we continue using the constraint data we extracted from V4.1.0 or have changes been made to how those metrics are calculated as well?

Thank you!

Starting with gnomAD v4.1.1, we no longer display constraint metrics for genes that have zero expected variants for at least one class of variation (synonymous, missense, or loss-of-function) as our models are likely not well calibrated for these genes. However, constraint metrics for all genes are available in our downloadable constraint files.

For example, the gene GJA3 is present in the constraint metrics TSV:

gene	gene_id	transcript	canonical	mane_select	transcript_version	transcript_type	transcript_level	chromosome	start_position	end_position	cds_length	num_coding_exons	gene_quality_metrics.exome_prop_bp_AN90gene_quality_metrics.exome_mean_AS_MQ	gene_quality_metrics.exome_prop_segdup	gene_quality_metrics.exome_prop_LCR	gene_flags	constraint_flags	syn.mu	syn.possible	syn.obs	syn.exp	syn.oe	syn.z_raw	syn.z_score	syn.oe_ci.lowersyn.oe_ci.upper	syn.gen_anc_obs.global	syn.gen_anc_obs.afr	syn.gen_anc_obs.amr	syn.gen_anc_obs.eas	syn.gen_anc_obs.nfe	syn.gen_anc_obs.sas	syn.gen_anc_exp.global	syn.gen_anc_exp.afr	syn.gen_anc_exp.amr	syn.gen_anc_exp.eas	syn.gen_anc_exp.nfe	syn.gen_anc_exp.sas	mis.mu	mis.possible	mis.obs	mis.exp	mis.oe	mis.z_raw	mis.z_score	mis.oe_ci.lower	mis.oe_ci.upper	mis.gen_anc_obs.global	mis.gen_anc_obs.afr	mis.gen_anc_obs.amr	mis.gen_anc_obs.eas	mis.gen_anc_obs.nfe	mis.gen_anc_obs.sas	mis.gen_anc_exp.global	mis.gen_anc_exp.afr	mis.gen_anc_exp.amr	mis.gen_anc_exp.eas	mis.gen_anc_exp.nfe	mis.gen_anc_exp.sas	lof_hc_lc.mu	lof_hc_lc.possible	lof_hc_lc.obs	lof_hc_lc.exp	lof_hc_lc.oe	lof_hc_lc.z_raw	lof_hc_lc.z_score	lof_hc_lc.oe_ci.lower	lof_hc_lc.oe_ci.upper	lof_hc_lc.gen_anc_obs.global	lof_hc_lc.gen_anc_obs.afr	lof_hc_lc.gen_anc_obs.amr	lof_hc_lc.gen_anc_obs.eas	lof_hc_lc.gen_anc_obs.nfe	lof_hc_lc.gen_anc_obs.sas	lof_hc_lc.gen_anc_exp.global	lof_hc_lc.gen_anc_exp.afr	lof_hc_lc.gen_anc_exp.amr	lof_hc_lc.gen_anc_exp.eas	lof_hc_lc.gen_anc_exp.nfe	lof_hc_lc.gen_anc_exp.sas	lof_hc_lc.pLI	lof_hc_lc.pNull	lof_hc_lc.pRec	lof.mu	lof.possible	lof.obs	lof.exp	lof.oe	lof.z_raw	lof.z_score	lof.oe_ci.lower	lof.oe_ci.upper	lof.oe_ci.upper_rank	lof.oe_ci.upper_bin_percentile	lof.oe_ci.upper_bin_decile	lof.oe_ci.upper_bin_sextile	lof.gen_anc_obs.global	lof.gen_anc_obs.afr	lof.gen_anc_obs.amr	lof.gen_anc_obs.eas	lof.gen_anc_obs.nfe	lof.gen_anc_obs.sas	lof.gen_anc_exp.global	lof.gen_anc_exp.afr	lof.gen_anc_exp.amr	lof.gen_anc_exp.eas	lof.gen_anc_exp.nfe	lof.gen_anc_exp.sas	lof.pLI	lof.pNull	lof.pRec
GJA3	ENSG00000121743	ENST00000241125	true	true	ENST00000241125.4	protein_coding	2	chr13	20138255	20161052	1305	1	1.0000e+00	5.9995e+01	0.0000e+00	0.0000e+00	[]	["no_exp_lof"]	1.1119e-05	958	297	2.9256e+02	1.0152e+00	-2.5973e-01	-1.5497e-01	9.2353e-01	1.1176e+00	[0,0,0,6,10,11,16,29,36,41,44,44,47,55,59,67,74,106,154,255,264]	[0,0,1,7,11,12,15,25,30,36]	[0,0,1,3,3,8,15,25,31,32,39,39,40]	[0,0,0,2,5,6,11,23,30,32,37]	[0,0,0,1,6,7,13,23,28,34,39,39,41,42,45,56,61,92,136,204,214]	[0,0,0,4,10,12,15,22,25,28,34,34,36,40,44,56]	[0.0,0.0,1.9758899499019127,6.439129798039037,11.816066183127015,15.672206365931729,23.179854055489614,36.78522698564073,43.47383764833371,50.34941086574893,55.64482846139212,55.87596053796935,59.49197531140357,65.7805438604783,70.26150461072159,84.5898393869103,91.17064883587607,127.35850038074153,173.0417004631954,252.6749053596242,263.4230553053693]	[0.0,0.0,2.361191836158085,6.610713692993698,11.938534287470095,15.631075258391958,23.020221990602572,35.780385434246924,41.98707190969526,48.39205406742485]	[0.0,0.0,2.2341621417681274,6.233203128961899,11.258220286117538,14.603291380852081,21.09230584327959,31.846563856072923,36.929259485352354,42.084462210377,45.920201076910935,46.092633393456104,48.727470092489796]	[0.0,0.0,1.996450315309638,5.228421235907664,9.406461960056898,12.236312423372135,17.93372939791319,27.968840374090128,32.932451148084795,38.17919618530159,42.21188996160309]	[0.0,0.0,1.6044707507637024,4.373801703208497,8.26164184524027,11.143542303712202,17.057038298040784,27.912340300138315,33.29122364727637,38.894660955753274,43.186967566583355,43.386448984130055,46.328755210905705,51.44892330746867,55.140541111668796,67.07855628634397,72.5139070965689,102.02965050009075,139.06505396909003,202.3404728029647,210.9768941710781]	[0.0,0.0,2.19287112092389,6.042312743270888,11.0277495790507,14.396833348932851,21.305952293726136,33.17149321591855,39.00169560257442,45.16494860928718,49.85212210199583,50.07784849414171,53.373515818331526,58.928381180532334,62.99367590959447,76.01768665564163]	1.9061e-05	2817	571	6.2032e+02	9.2050e-01	1.9802e+00	8.4452e-01	8.5962e-01	9.8643e-01	[0,0,2,5,7,11,14,30,41,47,58,58,67,77,83,101,113,190,282,468,496]	[0,0,0,7,9,20,26,47,54,62]	[0,0,0,3,6,10,15,30,35,40,45,45,52]	[0,0,0,5,8,14,20,31,43,54,64]	[0,0,1,3,5,7,11,28,32,47,50,50,53,59,62,78,86,146,215,351,373]	[0,0,0,7,13,15,26,38,44,53,57,58,60,67,72,95]	[0.0,0.0,3.5183868467425263,11.289967856708849,20.72823484388578,27.57565761204593,40.98102449427436,65.66691639845892,77.99285891015676,90.81156580478564,100.79430827990379,101.23005880500237,108.1158938437769,120.14616053385947,128.78831307649116,156.86385694237381,169.98171957669715,244.534297485504,343.40092275576484,525.2774944598704,550.671222435374]	[0.0,0.0,4.107134713771138,11.578974641710701,20.961187632954733,27.538002799388487,40.79167339737744,63.98823267353769,75.44976050895875,87.41035689618809]	[0.0,0.0,3.9051272256081595,10.922660958763391,19.787073665983907,25.73619252370945,37.279382564410966,56.65071808446767,65.92306093095486,75.38198905227604,82.523098171392,82.85323947554677,87.75524943026589]	[0.0,0.0,3.487179411502575,9.145393672478598,16.487277825262375,21.511723537553493,31.63359108905654,49.67391385569887,58.74042200861366,68.38781743795371,75.85586593888495]	[0.0,0.0,2.804097766705156,7.624990325271556,14.44102685578625,19.53014628565427,30.010525413199854,49.46857298467663,59.24216862729098,69.52687551023847,77.46539937638742,77.83903391553356,83.31670788301685,92.8783846032862,99.83192091845248,122.67990476983559,133.25729428365074,192.23551867833527,269.7752245727865,409.5468834144472,429.24701404681224]	[0.0,0.0,3.826734037017941,10.568537015398022,19.375424036443643,25.361261070777196,37.688410371644814,59.16002823287648,69.92821780376183,81.36629905882155,90.14790861264842,90.57480585078109,96.77235388167783,107.35262910386624,115.1530596114292,140.5205774506942]	5.3553e-07	131	20	2.7652e+01	7.2327e-01	1.4552e+00	1.2140e+00	5.0890e-01	1.0510e+00	[0,0,0,0,0,0,0,0,0,0,0,0,2,2,2,2,2,5,7,13,15]	[0,0,0,0,0,0,0,0,0,0]	[0,0,0,1,1,1,1,1,1,2,2,2,2]	[0,0,0,0,0,0,0,1,1,1,1]	[0,0,0,0,0,0,0,0,0,0,1,1,1,1,1,1,2,5,9,13,14]	[0,0,0,0,0,0,0,0,0,0,0,0,0,1,1,3]	[0.0,0.0,0.11246127293363643,0.3470140176625849,0.6385153269076647,0.8562782131793654,1.288450733503287,2.121076021426807,2.554052394383164,3.0157439707437663,3.3874120907945278,3.403593787962307,3.66369831201532,4.1224619587920905,4.459087503441511,5.5868009614120595,6.130522704641907,9.383436104147608,14.001182837762952,22.905569024471188,24.170575443836963]	[0.0,0.0,0.12320717720666341,0.3559874285012772,0.647328439987282,0.8576931817620491,1.2904365127270112,2.077860278005144,2.4834717589433346,2.915255921203858]	[0.0,0.0,0.11932922183257953,0.3367181223979546,0.6127680063778315,0.8024512405242019,1.1726402778261944,1.813551314147041,2.1313331761633947,2.4628560629688327,2.7172654787900736,2.7294605078856065,2.905235439265494]	[0.0,0.0,0.10572668389145634,0.2760541442580047,0.5004429558823751,0.6587211026623653,0.9799191319768323,1.569428159986623,1.8779157120234438,2.212670672280967,2.4776348909967663]	[0.0,0.0,0.0845190415846646,0.23010517660055904,0.43878255865217713,0.59708116886692,0.9272047131286482,1.5628636579335338,1.8916416694866478,2.2496533933041087,2.530528880471018,2.5437370629004676,2.7400235716943024,3.0874012292806863,3.343545784827301,4.21548519788601,4.633891268718942,7.0747637611144185,10.539812069465748,17.19484653789579,18.159037819882208]	[0.0,0.0,0.11684020266024858,0.32216016749106646,0.5947621394831762,0.7828735683606651,1.1801972853692477,1.9001126531205224,2.276239024170576,2.683118824522179,3.002703377041907,3.0180905813213252,3.2469539434303982,3.643767933886735,3.9396643276925776,4.940274777583184]	NA	NA	NA	4.6854e-09	3NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null]	[null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null]	NA	NA	NA

and is flagged with the following constraint flag: no_exp_lof.