rs28939070
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_014112.5(TRPS1):c.2894G>A(p.Arg965His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R965C) has been classified as Pathogenic.
Frequency
Consequence
NM_014112.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPS1 | NM_014112.5 | c.2894G>A | p.Arg965His | missense_variant | 7/7 | ENST00000395715.8 | |
TRPS1 | NM_001282903.3 | c.2873G>A | p.Arg958His | missense_variant | 7/7 | ||
TRPS1 | NM_001282902.3 | c.2867G>A | p.Arg956His | missense_variant | 6/6 | ||
TRPS1 | NM_001330599.2 | c.2855G>A | p.Arg952His | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPS1 | ENST00000395715.8 | c.2894G>A | p.Arg965His | missense_variant | 7/7 | 1 | NM_014112.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Trichorhinophalangeal dysplasia type I Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2004 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2022 | In vitro assays demonstrated primarily cytoplasmic localization and loss of nuclear localization (Elli et al., 2022; Kaiser et al., 2004); Not observed in large population cohorts (gnomAD); Also known as p.(R952H); This variant is associated with the following publications: (PMID: 34897794, 14560312, 25792522) - |
Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 965 of the TRPS1 protein (p.Arg965His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TRPS1 function (PMID: 14560312). 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 TRPS1 protein function. ClinVar contains an entry for this variant (Variation ID: 5580). This missense change has been observed in individuals with trichorhinophalangeal syndrome (PMID: 14560312; Invitae). It has also been observed to segregate with disease in related individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at