3-44901672-G-A

Variant names:

• chr3-44901672-G-A
• rs139860990
• NM_003241.4:c.806G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BS1_Supporting BS2_Supporting

The NM_003241.4(TGM4):​c.806G>A​(p.Trp269*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00785 in 1,614,152 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0079 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (98 hom.)
• Consequence: TGM4 NM_003241.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.43

Genes affected

TGM4 (HGNC:11780): (transglutaminase 4) Predicted to enable protein-glutamine gamma-glutamyltransferase activity. Predicted to be involved in peptide cross-linking. Predicted to act upstream of or within mating plug formation. Located in Golgi apparatus and collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant 3-44901672-G-A is Pathogenic according to our data. Variant chr3-44901672-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184858.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00785 (11475/1461816) while in subpopulation MID AF = 0.0359 (207/5768). AF 95% confidence interval is 0.0319. There are 98 homozygotes in GnomAdExome4. There are 6052 alleles in the male GnomAdExome4 subpopulation. Median coverage is 64. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM4	NM_003241.4	c.806G>A	p.Trp269*	stop_gained	Exon 7 of 14	ENST00000296125.9	NP_003232.2
TGM4	XM_011534042.3	c.941G>A	p.Trp314*	stop_gained	Exon 8 of 15		XP_011532344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM4	ENST00000296125.9	c.806G>A	p.Trp269*	stop_gained	Exon 7 of 14	1	NM_003241.4	ENSP00000296125.4
TGM4	ENST00000705784.1	c.941G>A	p.Trp314*	stop_gained	Exon 8 of 15			ENSP00000516167.1
TGM4	ENST00000422219.5	n.*423G>A		downstream_gene_variant		1		ENSP00000403711.1

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1203 AN: 152218 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00874

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00902 AC: 2266 AN: 251248 AF XY: 0.00990

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00746

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00920

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00785 AC: 11475 AN: 1461816 Hom.: 98 Cov.: 64 AF XY: 0.00832 AC XY: 6052 AN XY: 727196

Gnomad4 AFR exome AF: 0.00164 AC: 55 AN: 33478

Gnomad4 AMR exome AF: 0.00724 AC: 324 AN: 44722

Gnomad4 ASJ exome AF: 0.0216 AC: 564 AN: 26134

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39700

Gnomad4 SAS exome AF: 0.0148 AC: 1280 AN: 86258

Gnomad4 FIN exome AF: 0.0114 AC: 608 AN: 53382

Gnomad4 NFE exome AF: 0.00704 AC: 7833 AN: 1111982

Gnomad4 Remaining exome AF: 0.00997 AC: 602 AN: 60392

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152336 Hom.: 12 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74490

Gnomad4 AFR AF: 0.00132 AC: 0.00132301 AN: 0.00132301

Gnomad4 AMR AF: 0.0138 AC: 0.0137872 AN: 0.0137872

Gnomad4 ASJ AF: 0.0213 AC: 0.0213379 AN: 0.0213379

Gnomad4 EAS AF: 0.000193 AC: 0.00019305 AN: 0.00019305

Gnomad4 SAS AF: 0.0108 AC: 0.010775 AN: 0.010775

Gnomad4 FIN AF: 0.0119 AC: 0.0119496 AN: 0.0119496

Gnomad4 NFE AF: 0.00873 AC: 0.00873067 AN: 0.00873067

Gnomad4 OTH AF: 0.00851 AC: 0.00850662 AN: 0.00850662

Alfa AF: 0.00854 Hom.: 25

Bravo AF: 0.00799

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00834 AC: 1013

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0132

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Essential tremor Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Uncertain	0.27
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.055
GERP RS		1.9
Mutation Taster		=51/149	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139860990; hg19: chr3-44943164;