chr14-24255457-C-T

Position:

chr14-24255457-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000359.3(TGM1):c.1552G>A(p.Val518Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,614,116 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 18 hom., cov: 33)

Exomes 𝑓: 0.016 ( 212 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:10

Conservation

PhyloP100: 0.624

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077917576).

BP6

Variant 14-24255457-C-T is Benign according to our data. Variant chr14-24255457-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12496.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr14-24255457-C-T is described in Lovd as [Pathogenic]. Variant chr14-24255457-C-T is described in Lovd as [Likely_benign]. Variant chr14-24255457-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1661/152256) while in subpopulation NFE AF= 0.0185 (1261/68014). AF 95% confidence interval is 0.0177. There are 18 homozygotes in gnomad4. There are 771 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.1552G>A	p.Val518Met	missense_variant	11/15	ENST00000206765.11	NP_000350.1	P22735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.1552G>A	p.Val518Met	missense_variant	11/15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000544573.5 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	5/9	2		ENSP00000439446.1	P22735-2
TGM1	ENST00000559136.1 linkuse as main transcript	c.625G>A	p.Val209Met	missense_variant	7/7	5		ENSP00000453337.1	H0YLT9

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1661

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.0107

AC:

2691

AN:

251390

Hom.:

AF XY:

0.0108

AC XY:

1464

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00585

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0164

AC:

23995

AN:

1461860

Hom.:

212

Cov.:

AF XY:

0.0162

AC XY:

11748

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.00635

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00325

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0143

GnomAD4 genome

AF:

0.0109

AC:

1661

AN:

152256

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

771

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00335

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.00953

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0104

AC:

1264

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0176

EpiControl

AF:

0.0152

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:1Uncertain:1Benign:3

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Val518Met variant in TGM1 has been identified in at least 2 individuals with lamellar ichthyosis (PMID: 9545389), and has been identified in >1% of Euroopean (Finnish) chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for lamellar ichthyosis. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TGM1: BP4, BS1, 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

0.25

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.20

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.065

T;T;D

Sift4G

Benign

0.073

T;D;.

Polyphen

0.98

D;.;.

Vest4

0.17

MPC

0.83

ClinPred

0.019

GERP RS

4.9

Varity_R

0.15

gMVP

0.36

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