rs121908436
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_014112.5(TRPS1):c.2795C>T(p.Ala932Val) 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. 12/20 in silico tools predict a damaging 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. A932T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014112.5 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 |
---|---|---|---|---|---|---|---|
TRPS1 | NM_014112.5 | c.2795C>T | p.Ala932Val | missense_variant | 6/7 | ENST00000395715.8 | |
TRPS1 | NM_001282903.3 | c.2774C>T | p.Ala925Val | missense_variant | 6/7 | ||
TRPS1 | NM_001282902.3 | c.2768C>T | p.Ala923Val | missense_variant | 5/6 | ||
TRPS1 | NM_001330599.2 | c.2756C>T | p.Ala919Val | missense_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPS1 | ENST00000395715.8 | c.2795C>T | p.Ala932Val | missense_variant | 6/7 | 1 | NM_014112.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | TRPS1: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27706911, 25792522, 24502542, 18946009, 11950061, 28468609, 30541476, 30143558, 28426188) - |
Trichorhinophalangeal syndrome, type III Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Congenital anomaly of kidney and urinary tract Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 24, 2018 | - - |
Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 30, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 932 of the TRPS1 protein (p.Ala932Val). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala932 amino acid residue in TRPS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11112658, 30541476). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 5578). This missense change has been observed in individuals with tricho-rhino-phalangeal syndrome (PMID: 18946009, 24502542). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). - |
Trichorhinophalangeal dysplasia type I Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at