rs121918731

chr14-24259769-G-Achr14-24259769-G-Cchr14-24259769-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000359.3(TGM1):c.919C>T(p.Arg307Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,094 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. R307G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.23

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 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000359.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-24259769-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 372534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

PP5

Variant 14-24259769-G-A is Pathogenic according to our data. Variant chr14-24259769-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24259769-G-A is described in UniProt as null. Variant chr14-24259769-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.919C>T	p.Arg307Trp	missense_variant	6/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.919C>T	p.Arg307Trp	missense_variant	6/15	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000559136.1 linkuse as main transcript	c.-9C>T		5_prime_UTR_variant	2/7	5
TGM1	ENST00000544573.5 linkuse as main transcript	c.-28-1381C>T		intron_variant		2			P22735-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248966

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460950

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2001	- -
Pathogenic, criteria provided, single submitter	in vitro	Medical Genetics Laboratory, West China Hospital, Sichuan University	Jan 17, 2020	The newborn's entire body was covered with a thin transparent collodion membrane. Variant c.919 C>T was evaluated to be deleterious by PolyPhen-2, PROVEAN and Mutation Taster and amino acid was highly conserved in multiple species. Additionally, in vitro functional studies indicated that TGM1 protein expression levels significantly decreased in cells with c.919 C>T mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 26, 2018	- -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 23, 2022

Variant summary: TGM1 c.919C>T (p.Arg307Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248966 control chromosomes (gnomAD). c.919C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Lamellar Ichthyosis, predominantly from individuals of East Asian descent (e.g. Akiyama_2001, Muramatsu_2004, Sakai_2009, Yamamoto_2012, Yang_2001). These data indicate that the variant is very likely to be associated with disease. When TGase 1 activity was assayed in cultured keratocytes from a compound heterozygous proband and their unaffected carrier parent, there was 5% activity in the proband and 50% activity in the carrier parent, suggesting the variant may have limited functionality (Yang_2001). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg307 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16968736, 19863506, 26076875, 27025581, 28403434). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGM1 protein function. ClinVar contains an entry for this variant (Variation ID: 12499). This missense change has been observed in individuals with lamellar ichthyosis and self-improving collodion ichthyosis (PMID: 11407995, 11511296, 19262603, 20167857, 21895619, 24419105). This variant is present in population databases (rs121918731, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 307 of the TGM1 protein (p.Arg307Trp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.23

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.81

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.81

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.60

MVP

0.94

MPC

0.92

ClinPred

0.93

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.29

gMVP

0.70

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