rs760429286

Positions:

chr14-24262121-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000359.3(TGM1):c.232C>T(p.Arg78Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,482 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TGM1
NM_000359.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.736

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-24262121-G-A is Pathogenic according to our data. Variant chr14-24262121-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 449511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24262121-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.232C>T	p.Arg78Ter	stop_gained	2/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.232C>T	p.Arg78Ter	stop_gained	2/15	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000558074.1 linkuse as main transcript	c.232C>T	p.Arg78Ter	stop_gained	3/4	5
TGM1	ENST00000544573.5 linkuse as main transcript	c.-29+6C>T		splice_donor_region_variant, intron_variant		2			P22735-2
TGM1	ENST00000560443.1 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250334

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0000618

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:

0.0000462

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000189

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000449511, PMID:7581379, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 22, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7581379, 23895935) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 15, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449511). This premature translational stop signal has been observed in individual(s) with lamellar ichthyosis (PMID: 7581379). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760429286, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg78*) in the TGM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGM1 are known to be pathogenic (PMID: 18948357, 19241467). -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 25, 2019

Variant summary: TGM1 c.232C>T (p.Arg78X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 1.2e-05 in 250334 control chromosomes. c.232C>T has been reported in the literature in individuals affected with Lamellar ichthyosis, including two affected brothers from the same family (Parmentier_1995, Sugiura_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

TGM1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The TGM1 c.232C>T variant is predicted to result in premature protein termination (p.Arg78*). This variant has been reported in the homozygous state in several individuals with ichthyosis (Parmentier et al. 1995. PubMed ID: 7581379; Khan et al. 2023. PubMed ID: 36789964); and, it has been observed to co-segregate with disease in the affected family members (same studies). It has also been reported in the compound heterozygous state in a mildly affected patient along with a second TGM1 missense variant of uncertain significance (Sugiura et al. 2013. PubMed ID: 23895935). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in TGM1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

0.010

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.38

MutationTaster

Benign

1.0

A;N

Vest4

0.60

GERP RS

1.2

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