chrX-53533365-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_031407.7(HUWE1):c.13069C>T(p.Arg4357Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,206,317 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_031407.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HUWE1 | NM_031407.7 | c.13069C>T | p.Arg4357Cys | missense_variant | Exon 84 of 84 | ENST00000262854.11 | NP_113584.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000900 AC: 1AN: 111116Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33316
GnomAD4 exome AF: 9.13e-7 AC: 1AN: 1095201Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 360631
GnomAD4 genome AF: 0.00000900 AC: 1AN: 111116Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33316
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4357 of the HUWE1 protein (p.Arg4357Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HUWE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1195142). 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 HUWE1 protein function with a positive predictive value of 95%. 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 observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
HUWE1-related disorder Uncertain:1
The HUWE1 c.13069C>T variant is predicted to result in the amino acid substitution p.Arg4357Cys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Of note, a different substitution at the same codon, defined as c.13070G>A (p.Arg4357His), was reported in a newborn with syndromic presentation including blepharophimosis, sparse eyebrow, micrognathia, nystagmus, muscular, hypotonia of the trunk, broad hallux, clinodactyly of the 5th finger, primitive reflexes, and supernumerary nipple, but this individual also has a likely pathogenic variant in SOX11 (eTable 3, Lunke et al. 2020. PubMed ID: 32573669). At this time, the clinical significance of the c.13069C>T (p.Arg4357Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at