14-24249390-C-T

Position:

chr14-24249390-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_000359.3(TGM1):c.2377G>A(p.Gly793Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: -2.44

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 -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02632612).

BP6

Variant 14-24249390-C-T is Benign according to our data. Variant chr14-24249390-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 991479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.2377G>A	p.Gly793Arg	missense_variant	15/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.2377G>A	p.Gly793Arg	missense_variant	15/15	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000544573.5 linkuse as main transcript	c.1051G>A	p.Gly351Arg	missense_variant	9/9	2			P22735-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251342

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 17, 2020

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.011

DANN

Benign

0.40

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0045

M_CAP

Benign

0.022

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.085

Sift

Benign

0.52

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0

B;.

Vest4

0.12

MutPred

0.13

Loss of sheet (P = 0.0817);.;

MVP

0.40

MPC

0.31

ClinPred

0.044

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.031

gMVP

0.38

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