14-24258667-C-T

Position:

chr14-24258667-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000359.3(TGM1):c.1166G>A(p.Arg389His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R389P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.65

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.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-24258667-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 14-24258667-C-T is Pathogenic according to our data. Variant chr14-24258667-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24258667-C-T is described in UniProt as null. Variant chr14-24258667-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3 linkuse as main transcript	c.1166G>A	p.Arg389His	missense_variant	8/15	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.1166G>A	p.Arg389His	missense_variant	8/15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000559136.1 linkuse as main transcript	c.239G>A	p.Arg80His	missense_variant	4/7	5		ENSP00000453337.1	H0YLT9
TGM1	ENST00000544573.5 linkuse as main transcript	c.-28-279G>A		intron_variant		2		ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

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:

0.00

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:

0.0000159

AC:

AN:

251132

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000541

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

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:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 25, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16968736, 11251583, 10914678, 34908195, 38374194, 35734965, 36262015, 27025581, 19241467, 14996130, 23278109) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2023	This variant disrupts the p.Arg389 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10914678, 16968736, 19241467). 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. 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. ClinVar contains an entry for this variant (Variation ID: 12489). This variant is also known as R388H. This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 11251583, 14996130, 23278109, 27025581). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918723, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the TGM1 protein (p.Arg389His). -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 23, 2024

Variant summary: TGM1 c.1166G>A (p.Arg389His) 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 1.6e-05 in 251132 control chromosomes (gnomAD). c.1166G>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (e.g. Akiyama_2001, Hake_2022, Saat_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11251583, 34908195, 35734965). ClinVar contains an entry for this variant (Variation ID: 12489). Based on the evidence outlined above, the variant was classified as pathogenic. -

Abnormality of the skin

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.92

Loss of methylation at R389 (P = 0.0202);.;

MVP

0.99

MPC

1.0

ClinPred

1.0

GERP RS

4.5

Varity_R

0.96

gMVP

0.98

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