14-24262228-G-T

Position:

chr14-24262228-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000206765.11(TGM1):c.125C>A(p.Ser42Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,613,880 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S42S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 34 hom. )

Consequence

TGM1
ENST00000206765.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6O:1

Conservation

PhyloP100: 2.21

Variant links:

Genes affected

TGM1 (HGNC:11777): (transglutaminase 1) The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3' UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). [provided by RefSeq, Jul 2008]

TGM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010242194).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00415 (632/152340) while in subpopulation NFE AF= 0.006 (408/68036). AF 95% confidence interval is 0.00552. There are 7 homozygotes in gnomad4. There are 309 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.125C>A	p.Ser42Tyr	missense_variant	2/15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.125C>A	p.Ser42Tyr	missense_variant	2/15	1	NM_000359.3	ENSP00000206765	P1	P22735-1

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

632

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00600

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00427

AC:

1072

AN:

251102

Hom.:

AF XY:

0.00411

AC XY:

558

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.00636

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00665

Gnomad NFE exome

AF:

0.00579

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00550

AC:

8039

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

3849

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00532

Gnomad4 ASJ exome

AF:

0.00589

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00673

Gnomad4 NFE exome

AF:

0.00618

Gnomad4 OTH exome

AF:

0.00586

GnomAD4 genome

AF:

0.00415

AC:

632

AN:

152340

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

309

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00668

Gnomad4 NFE

AF:

0.00600

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00519

Hom.:

Bravo

AF:

0.00366

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00399

AC:

484

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:1Uncertain:1Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Uncertain significance and reported on 01-16-2019 by Lab or GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 27, 1995	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 02, 2024	The p.Ser42Tyr variant in TGM1 is classified as likely benign because it has been identified in 1.3% (4/316) of Middle Eastern and 0.67% (71/10628) of European Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is greater than the expected frequency of a pathogenic TGM1 variant causing disease. In addition, in vitro functional studies provide some evidence that this variant does not impact or increases protein expression (Candi 1998 PMID: 9593710, Numata 2016 PMID: 26990434). ACMG/AMP Criteria applied: BS1, BS3_Supporting. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TGM1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;T;T;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.52

M_CAP

Benign

0.045

MetaRNN

Benign

0.0099

T;T;T;T;T

MetaSVM

Uncertain

0.017

MutationAssessor

Benign

0.55

N;.;.;.;.

MutationTaster

Benign

0.79

A;A

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.33

N;N;D;D;D

REVEL

Uncertain

0.56

Sift

Benign

0.058

T;D;D;D;D

Sift4G

Uncertain

0.017

D;D;.;.;D

Polyphen

0.98

D;.;.;.;.

Vest4

0.54

MVP

0.97

MPC

0.81

ClinPred

0.011

GERP RS

4.7

Varity_R

0.14

gMVP

0.75

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