rs142634031

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000359.3(TGM1):c.877-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,612,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

TGM1
NM_000359.3 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 7.95

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.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02180114 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 14-24259813-T-C is Pathogenic according to our data. Variant chr14-24259813-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 279911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24259813-T-C 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.877-2A>G		splice_acceptor_variant		ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11 linkuse as main transcript	c.877-2A>G	splice_acceptor_variant	1	NM_000359.3	P1	P22735-1
TGM1	ENST00000559136.1 linkuse as main transcript	c.-51-2A>G	splice_acceptor_variant	5
TGM1	ENST00000544573.5 linkuse as main transcript	c.-28-1425A>G	intron_variant	2			P22735-2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000313

AC:

AN:

248880

Hom.:

AF XY:

0.000304

AC XY:

AN XY:

134966

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000952

Gnomad NFE exome

AF:

0.000596

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000537

AC:

785

AN:

1460890

Hom.:

Cov.:

AF XY:

0.000493

AC XY:

358

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000152

Gnomad4 NFE exome

AF:

0.000673

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000263

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000452

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000594

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive congenital ichthyosis 1 (MIM#242300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Functional studies showed this variant resulted in abnormal splicing and predicted to result in premature protein termination (PMID: 10914678). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (85 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in individuals with ichthyosis (ClinVar, PMID: 7824952, PMID: 10914678, PMID: 16968736). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.790C>T) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 18, 2021	NM_000359.2(TGM1):c.877-2A>G is a canonical splice variant classified as pathogenic in the context of TGM1-related autosomal recessive congenital ichthyosis. c.877-2A>G has been observed in cases with relevant disease (PMID: 9545389, 9887377, 19241467). Functional assessments of this variant are available in the literature (PMID: 9887377). c.877-2A>G has been observed in population frequency databases (gnomAD: NFE 0.06%). In summary, NM_000359.2(TGM1):c.877-2A>G is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change affects an acceptor splice site in intron 5 of the TGM1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs142634031, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with congenital ichthyosis (PMID: 7824952, 10914678, 19241467, 27025581, 28403434). ClinVar contains an entry for this variant (Variation ID: 279911). Studies have shown that disruption of this splice site results in inclusion of intron 5 or an insertion of a single nucleotide between exons 5 and 6 and introduces a premature termination codon (PMID: 7824952, 10914678). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 06, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	One of the most common TGM1 pathogenic variants causing lamellar ichthyosis, and accounts for approximately one third of all disease-associated alleles among individuals with TGM1-related ichthyosis worldwide (Herman et al., 2009); Canonical splice site variant shown to lead to abnormal splicing and almost complete elimination of transglutaminase 1 enzyme function (Huber et al., 1997; Herman et al., 2009) in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9544844, 10694685, 11298529, 9359043, 16968736, 7824952, 9887377, 10914678, 27025581, 9261103, 29444371, 22437313, 19241467, 28403434, 31168818, 15665393, 31642606, 31980526, 31589614) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

TGM1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

The TGM1 c.877-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive congenital ichthyosis (see for example, Sitek et al. 2018. PubMed ID: 29444371; Table 2a, Seidl-Philipp et al. 2020. PubMed ID: 31642606; Pigg et al. 2016. PubMed ID: 27025581; Simpson et al. 2020. PubMed ID: 31168818). This variant is reported in 0.057% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has been reported as a founder variant in Norway (Pigg et al. 2016. PubMed ID: 27025581). Variants that disrupt the consensus splice acceptor site in TGM1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Autosomal recessive congenital ichthyosis

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: -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