rs121918722

Positions:

• chr14-24259087-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000206765.11(TGM1):​c.1147G>A​(p.Val383Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,746 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGM1 ENST00000206765.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in ENST00000206765.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 14-24259087-C-T is Pathogenic according to our data. Variant chr14-24259087-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24259087-C-T is described in UniProt as null. Variant chr14-24259087-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM1	NM_000359.3	c.1147G>A	p.Val383Met	missense_variant	7/15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.1147G>A	p.Val383Met	missense_variant	7/15	1	NM_000359.3	ENSP00000206765	P1
TGM1	ENST00000559136.1	c.220G>A	p.Val74Met	missense_variant	3/7	5		ENSP00000453337
TGM1	ENST00000544573.5	c.-28-699G>A		intron_variant		2		ENSP00000439446

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	Homozygous missense variation in exon 7 of TGM1 gene that result in amino acid substitution of methionine for valine at codon 383 was detected. This variant has not been reported in 1000 genome and genomAD database. The insilico prediction of the variant are probably damaging by ployphen-2 (HumDiv)and damaging by SIFT, LRT and mutationTaster2. The reference codon is conserved across species. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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 congenital ichthyosis 1 (MIM#242300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated catalytic core domain (PMID: 22801880). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with lamellar ichthyosis and bathing suit ichthyosis (PMID: 9359043, 23096117, 22801880, 30693114). It has also been reported multiple times as pathogenic/likely pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using cultured keratinocyotes from affected patient exhibited reduced transglutaminase activity and an absence of TGK protein (PMID: 9359043). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Abnormality of the skin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Lamellar ichthyosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 05, 2021

Variant summary: TGM1 c.1147G>A (p.Val383Met) results in a conservative amino acid change located in the Transglutaminase-like domain (IPR002931) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250736 control chromosomes. c.1147G>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (example, Petit_1997, Terrinoni_2012, Satishkumar_2018, Li_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal transglutaminase type 1 enzyme activity (example, Petit_1997). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

TGM1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2023

The TGM1 c.1147G>A variant is predicted to result in the amino acid substitution p.Val383Met. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive congenital ichthyosis (reported as Val382Met in Petit et al. 1997. PubMed ID: 9359043; Bourrat et al. 2012. PubMed ID: 22801880; Terrinoni et al. 2012. PubMed ID: 23096117. Sathishkumar et al. 2018. PubMed ID: 30693114; Chiramel et al. 2022. PubMed ID: 35412663). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 383 of the TGM1 protein (p.Val383Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGM1-related conditions (PMID: 9359043, 22801880, 23096117, 30693114). ClinVar contains an entry for this variant (Variation ID: 12488). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.69		Loss of catalytic residue at V383 (P = 0.0049);.;
MVP		0.97
MPC		0.92
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.70
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121918722; hg19: chr14-24728293;