chr14-24255450-T-C

Position:

chr14-24255450-T-C

Variant summary

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

The NM_000359.3(TGM1):c.1559A>G(p.Glu520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,614,004 control chromosomes in the GnomAD database, including 69 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 0.0053 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 64 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.59

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=0.0060895383).

BP6

Variant 14-24255450-T-C is Benign according to our data. Variant chr14-24255450-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr14-24255450-T-C is described in UniProt as null. Variant chr14-24255450-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00534 (813/152118) while in subpopulation NFE AF= 0.00918 (624/67996). AF 95% confidence interval is 0.00858. There are 5 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.1559A>G	p.Glu520Gly	missense_variant	11/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.1559A>G	p.Glu520Gly	missense_variant	11/15	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000544573.5 linkuse as main transcript	c.233A>G	p.Glu78Gly	missense_variant	5/9	2			P22735-2
TGM1	ENST00000559136.1 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00535

AC:

813

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00160

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00623

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00918

Gnomad OTH

AF:

0.00624

GnomAD3 exomes

AF:

0.00571

AC:

1435

AN:

251384

Hom.:

AF XY:

0.00564

AC XY:

766

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.00661

Gnomad NFE exome

AF:

0.00963

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00826

AC:

12070

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

5886

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.00584

Gnomad4 NFE exome

AF:

0.00997

Gnomad4 OTH exome

AF:

0.00555

GnomAD4 genome

AF:

0.00534

AC:

813

AN:

152118

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

389

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00623

Gnomad4 NFE

AF:

0.00918

Gnomad4 OTH

AF:

0.00618

Alfa

AF:

0.00795

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00567

AC:

688

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00802

EpiControl

AF:

0.00984

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TGM1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 31642606, 27025581, 11348475, 21228398) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive congenital ichthyosis 1

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 21, 2022

- -

TGM1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as likely 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

0.30

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.63

M_CAP

Benign

0.060

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

0.72

D;D

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.52

Sift

Benign

0.085

T;D

Sift4G

Benign

0.086

T;T

Polyphen

0.96

P;.

Vest4

0.21

MVP

0.93

MPC

0.98

ClinPred

0.036

GERP RS

5.4

Varity_R

0.34

gMVP

0.58

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