chr14-77428468-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_001193315.2(VIPAS39):c.1363C>T(p.Arg455Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000447 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001193315.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 151996Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251090Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135708
GnomAD4 exome AF: 0.000473 AC: 692AN: 1461534Hom.: 0 Cov.: 32 AF XY: 0.000447 AC XY: 325AN XY: 727076
GnomAD4 genome AF: 0.000197 AC: 30AN: 151996Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74232
ClinVar
Submissions by phenotype
not provided Uncertain:2
- -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 455 of the VIPAS39 protein (p.Arg455Trp). This variant is present in population databases (rs149168488, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with VIPAS39-related conditions. ClinVar contains an entry for this variant (Variation ID: 497773). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VIPAS39 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. -
not specified Uncertain:1
Variant summary: VIPAS39 c.1363C>T (p.Arg455Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251090 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1363C>T in individuals affected with Arthrogryposis, Renal Dysfunction, And Cholestasis 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The c.1363C>T (p.R455W) alteration is located in exon 19 (coding exon 18) of the VIPAS39 gene. This alteration results from a C to T substitution at nucleotide position 1363, causing the arginine (R) at amino acid position 455 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Arthrogryposis, renal dysfunction, and cholestasis 2 Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at