rs397515485
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_005334.3(HCFC1):c.344C>T(p.Ala115Val) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A115T) has been classified as Uncertain significance.
Frequency
Consequence
NM_005334.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCFC1 | NM_005334.3 | c.344C>T | p.Ala115Val | missense_variant, splice_region_variant | 3/26 | ENST00000310441.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCFC1 | ENST00000310441.12 | c.344C>T | p.Ala115Val | missense_variant, splice_region_variant | 3/26 | 1 | NM_005334.3 | P2 | |
HCFC1 | ENST00000369984.4 | c.344C>T | p.Ala115Val | missense_variant, splice_region_variant | 3/26 | 5 | A2 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1059455Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 335791
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Methylmalonic acidemia with homocystinuria, type cblX Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Mar 21, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 05, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the HCFC1 protein (p.Ala115Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cobalamin X deficiency (PMID: 24011988, 28363510). ClinVar contains an entry for this variant (Variation ID: 66984). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HCFC1 function (PMID: 28449119). For these reasons, this variant has been classified as Pathogenic. - |
Disorders of Intracellular Cobalamin Metabolism 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