chr14-24259944-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.872G>A(p.Gly291Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,882 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G291S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000359.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.872G>A | p.Gly291Asp | missense_variant | 5/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.872G>A | p.Gly291Asp | missense_variant | 5/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000559136.1 | c.-56G>A | 5_prime_UTR_variant | 1/7 | 5 | ||||
TGM1 | ENST00000544573.5 | c.-28-1556G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251344Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461674Hom.: 0 Cov.: 33 AF XY: 0.0000536 AC XY: 39AN XY: 727160
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 04, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31168818, 18948357, 27025581, 19863506, 20137757, 19241467) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 291 of the TGM1 protein (p.Gly291Asp). This variant is present in population databases (rs780990272, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 19241467, 19863506, 27025581, 28403434). ClinVar contains an entry for this variant (Variation ID: 265269). 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. This variant disrupts the p.Gly291 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19262603, 30600594). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at