Variant 20-2317144-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_003245.4(TGM3):c.746G>A(p.Ser249Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,926 control chromosomes in the GnomAD database, including 11,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.13 ( 1509 hom., cov: 31)

Exomes 𝑓: 0.11 ( 9498 hom. )

Consequence

TGM3
NM_003245.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.243

Variant links:

Genes affected

TGM3 (HGNC:11779): (transglutaminase 3) Transglutaminases are enzymes that catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. While the primary structure of transglutaminases is not conserved, they all have the same amino acid sequence at their active sites and their activity is calcium-dependent. The protein encoded by this gene consists of two polypeptide chains activated from a single precursor protein by proteolysis. The encoded protein is involved the later stages of cell envelope formation in the epidermis and hair follicle. [provided by RefSeq, Jul 2008]

TGM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022105575).

BP6

Variant 20-2317144-G-A is Benign according to our data. Variant chr20-2317144-G-A is described in ClinVar as [Benign]. Clinvar id is 3061032.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM3	NM_003245.4 linkuse as main transcript	c.746G>A	p.Ser249Asn	missense_variant	6/13	ENST00000381458.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM3	ENST00000381458.6 linkuse as main transcript	c.746G>A	p.Ser249Asn	missense_variant	6/13	1	NM_003245.4	P1
TGM3	ENST00000463090.1 linkuse as main transcript	n.126G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20168

AN:

152046

Hom.:

1490

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.0840

Gnomad SAS

AF:

0.0621

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.109

AC:

27313

AN:

251338

Hom.:

1667

AF XY:

0.107

AC XY:

14570

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.0855

Gnomad ASJ exome

AF:

0.125

Gnomad EAS exome

AF:

0.0792

Gnomad SAS exome

AF:

0.0683

Gnomad FIN exome

AF:

0.113

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.111

AC:

161571

AN:

1461762

Hom.:

9498

Cov.:

AF XY:

0.110

AC XY:

79685

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.199

Gnomad4 AMR exome

AF:

0.0856

Gnomad4 ASJ exome

AF:

0.124

Gnomad4 EAS exome

AF:

0.0732

Gnomad4 SAS exome

AF:

0.0679

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.113

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.133

AC:

20219

AN:

152164

Hom.:

1509

Cov.:

AF XY:

0.130

AC XY:

9654

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.105

Gnomad4 ASJ

AF:

0.127

Gnomad4 EAS

AF:

0.0834

Gnomad4 SAS

AF:

0.0626

Gnomad4 FIN

AF:

0.109

Gnomad4 NFE

AF:

0.116

Gnomad4 OTH

AF:

0.143

Alfa

AF:

0.118

Hom.:

1907

Bravo

AF:

0.136

TwinsUK

AF:

0.104

AC:

386

ALSPAC

AF:

0.104

AC:

399

ESP6500AA

AF:

0.200

AC:

881

ESP6500EA

AF:

0.115

AC:

992

ExAC

AF:

0.112

AC:

13611

Asia WGS

AF:

0.133

AC:

465

AN:

3478

EpiCase

AF:

0.113

EpiControl

AF:

0.115

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TGM3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.7

DANN

Benign

0.51

DEOGEN2

Benign

0.23

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.021

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.015

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

0.35

REVEL

Benign

0.22

Sift

Benign

0.59

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.012

MPC

0.074

ClinPred

0.00071

GERP RS

-0.39

Varity_R

0.13

gMVP

0.095

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over