rs121918723
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000359.3(TGM1):āc.1166G>Cā(p.Arg389Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,026 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389H) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.1166G>C | p.Arg389Pro | missense_variant | 8/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.1166G>C | p.Arg389Pro | missense_variant | 8/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000559136.1 | c.239G>C | p.Arg80Pro | missense_variant | 4/7 | 5 | |||
TGM1 | ENST00000544573.5 | c.-28-279G>C | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251132Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135798
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461854Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4AN XY: 727220
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 11, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2023 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 389 of the TGM1 protein (p.Arg389Pro). This variant is present in population databases (rs121918723, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 16968736, 19241467). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 838484). 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%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19212342). 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