rs143473912

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_000359.3(TGM1):c.944G>T(p.Arg315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,611,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.56

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 Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-24259745-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

PP5

Variant 14-24259744-C-A is Pathogenic according to our data. Variant chr14-24259744-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24259744-C-A is described in UniProt as null. Variant chr14-24259744-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.944G>T	p.Arg315Leu	missense_variant	6/15	ENST00000206765.11	NP_000350.1	P22735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TGM1	ENST00000206765.11 link	c.944G>T	p.Arg315Leu	missense_variant	6/15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000559136.1 link	c.17G>T	p.Arg6Leu	missense_variant	2/7	5		ENSP00000453337.1	H0YLT9
TGM1	ENST00000544573.5 link	c.-28-1356G>T		intron_variant		2		ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

246144

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133622

show subpopulations

Gnomad AFR exome

AF:

0.000572

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1459718

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726038

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000191

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000628

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000151

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 22, 2018	The TGM1 c.944G>T (p.Arg315Leu) missense variant has been reported in three studies in which it is found in a total of 11 individuals with congenital ichthyosis including in ten in a homozygous state and in one in a compound heterozygous state (Tok et al. 1999; Arita et al. 2007; Hackett et al. 2010). The variant is also found in one unaffected parent in a heterozygous state (Tok et al. 1999). The p.Arg315Leu variant has been associated with a specific phenotype of ichthyosis referred to as bathing suit ichthyosis (Arita et al. 2007; Hackett et al. 2010). The p.Arg315Leu variant was absent from at least 150 control chromosomes (Arita et al. 2007; Hackett et al. 2010) and is reported at a frequency of 0.00061 in the African population of the Exome Aggregation Consortium. Testing in NHEK cells found that the p.Arg315Leu variant demonstrated increased protein stability, increased half-life and prevented proteolytic processing into the active form of the enzyme (Candi et al. 1998). The specific activity of the unprocessed form was similar to wild type, however due to the lack of processing the variant protein could not be converted into the highly active form, unlike wild type (Candi et al. 1998). The Arg315 residue is highly conserved and is located in a catalytic core domain (Arita et al. 2007). Based on the evidence, the p.Arg315Leu variant is classified as pathogenic for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2023	Published functional studies demonstrate a damaging effect with impaired proteolytic processing, reduced activity of membrane-bound transglutaminase 1 in keratinocytes, and enhanced stability of the mutant protein; variant described using alternate nomenclature as R314L (Candi et al., 1998; Trindade et al., 2010); This variant is associated with the following publications: (PMID: 31168818, 28403434, 19863506, 20522418, 10232404, 31589614, 35698621, 16977323, 9593710) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 315 of the TGM1 protein (p.Arg315Leu). This variant is present in population databases (rs143473912, gnomAD 0.06%). This missense change has been observed in individuals with TGM1-related disease (PMID: 10232404, 16977323, 19863506, 20522418, 28403434). ClinVar contains an entry for this variant (Variation ID: 39531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGM1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 9593710). This variant disrupts the p.Arg315 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10232404, 16977323, 19863506, 20522418, 28403434). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

TGM1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The TGM1 c.944G>T variant is predicted to result in the amino acid substitution p.Arg315Leu. This variant has been previously reported in the homozygous or compound heterozygous state in patients with ichthyosis (Arita et al. 2007. PubMed ID: 16977323; Trindade et al. 2010. PubMed ID: 20522418; Hackett et al. 2010. PubMed ID: 19863506; Table S2, Simpson et al 2019. PubMed ID: 31168818; Marukian et al 2017. PubMed ID: 28403434). This variant is reported in 0.053% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.85

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.9

M;.

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.059

T;.

Polyphen

0.99

D;.

Vest4

0.97

MVP

0.98

MPC

1.0

ClinPred

0.83

GERP RS

4.9

Varity_R

0.62

gMVP

0.85

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