8-115414111-G-A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2
The NM_014112.5(TRPS1):c.3797C>T(p.Thr1266Met) variant causes a missense change. The variant allele was found at a frequency of 0.000151 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1266T) has been classified as Likely benign.
Frequency
Consequence
NM_014112.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPS1 | NM_014112.5 | c.3797C>T | p.Thr1266Met | missense_variant | 7/7 | ENST00000395715.8 | |
TRPS1 | NM_001282903.3 | c.3776C>T | p.Thr1259Met | missense_variant | 7/7 | ||
TRPS1 | NM_001282902.3 | c.3770C>T | p.Thr1257Met | missense_variant | 6/6 | ||
TRPS1 | NM_001330599.2 | c.3758C>T | p.Thr1253Met | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPS1 | ENST00000395715.8 | c.3797C>T | p.Thr1266Met | missense_variant | 7/7 | 1 | NM_014112.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000724 AC: 11AN: 151942Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000683 AC: 17AN: 249040Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135092
GnomAD4 exome AF: 0.000159 AC: 232AN: 1461702Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 107AN XY: 727146
GnomAD4 genome AF: 0.0000724 AC: 11AN: 151942Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7AN XY: 74182
ClinVar
Submissions by phenotype
Trichorhinophalangeal dysplasia type I;C1860823:Trichorhinophalangeal syndrome, type III Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1266 of the TRPS1 protein (p.Thr1266Met). This variant is present in population databases (rs376875568, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1347607). 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 not expected to disrupt TRPS1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at