rs201853046
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000359.3(TGM1):c.2290C>T(p.Arg764Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,932 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
TGM1
NM_000359.3 missense
NM_000359.3 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 5.71
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
Variant 14-24249477-G-A is Pathogenic according to our data. Variant chr14-24249477-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552621.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=2}. Variant chr14-24249477-G-A is described in UniProt as null. Variant chr14-24249477-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.2290C>T | p.Arg764Cys | missense_variant | 15/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.2290C>T | p.Arg764Cys | missense_variant | 15/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000544573.5 | c.964C>T | p.Arg322Cys | missense_variant | 9/9 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251208Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135818
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461822Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 727206
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74282
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGM1 related disorder (ClinVar ID: VCV000552621, PMID:16908342, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23621129, PM3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.717, PP3_P). Missense changes are a common disease-causing mechanism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000021, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 29, 2024 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16908342, 23621129, 26620441, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 764 of the TGM1 protein (p.Arg764Cys). This variant is present in population databases (rs201853046, gnomAD 0.02%). This missense change has been observed in individual(s) with TGM1-related conditions (PMID: 16908342, 23621129, 33786896). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552621). 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. For these reasons, this variant has been classified as Pathogenic. - |
TGM1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 20, 2023 | The TGM1 c.2290C>T variant is predicted to result in the amino acid substitution p.Arg764Cys. This variant was reported in homozygous and compound heterozygous state in several individuals with Ichthyosis (Mizrachi-Koren et al. 2006. PubMed ID: 16908342; Table 1, Israeli et al. 2013. PubMed ID: 23621129; Table S3, Mohamad et al. 2021. PubMed ID: 33786896). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-24718683-G-A). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at P763 (P = 0.0193);.;
MVP
MPC
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at