rs121918725
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1PM2PM5PP3PP5_Very_Strong
The NM_000359.3(TGM1):c.832G>A(p.Gly278Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G278A) 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 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.832G>A | p.Gly278Arg | missense_variant | 5/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.832G>A | p.Gly278Arg | missense_variant | 5/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000559136.1 | c.-96G>A | 5_prime_UTR_variant | 1/7 | 5 | ||||
TGM1 | ENST00000544573.5 | c.-28-1596G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251426Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135906
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74358
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:7
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Jun 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Likely 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 | literature only | OMIM | Feb 01, 2003 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 02, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 278 of the TGM1 protein (p.Gly278Arg). This variant is present in population databases (rs121918725, gnomAD 0.006%). This missense change has been observed in individuals with TGM1-related conditions (PMID: 22311480, 23689228, 28403434). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12492). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | Biochemical assays of transglutaminase 1 with the amino acid substitution demonstrated markedly reduced activity of the epidermal transglutaminase 1 protein (Raghunath et al., 2003); This variant is associated with the following publications: (PMID: 12542526, 11298529, 22311480, 23689228, 30693114, 28403434) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at