rs757976755
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_014362.4(HIBCH):c.196C>T(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_014362.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HIBCH | NM_014362.4 | c.196C>T | p.Arg66Trp | missense_variant | 3/14 | ENST00000359678.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HIBCH | ENST00000359678.10 | c.196C>T | p.Arg66Trp | missense_variant | 3/14 | 1 | NM_014362.4 | P1 | |
HIBCH | ENST00000392332.7 | c.196C>T | p.Arg66Trp | missense_variant | 3/13 | 1 | |||
HIBCH | ENST00000409934.1 | c.358C>T | p.Arg120Trp | missense_variant | 3/8 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251378Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135876
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461612Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727140
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Beta-hydroxyisobutyryl-CoA deacylase deficiency Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2015 | - - |
Pathogenic, no assertion criteria provided | research | Bonnen Lab, Baylor College of Medicine | Dec 30, 2014 | Decreased HIBCH enzymatic activity in fibroblasts. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2018 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported as homozygous in an individual affected with 3-Hydroxyisobutryl-CoA hydrolase deficiency (PMID: 26026795). ClinVar contains an entry for this variant (Variation ID: 190268). This variant is present in population databases (rs757976755, ExAC 0.003%). This sequence change replaces arginine with tryptophan at codon 66 of the HIBCH protein (p.Arg66Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at