rs730880030
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_213720.3(CHCHD10):c.44G>T(p.Arg15Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15S) has been classified as Uncertain significance.
Frequency
Consequence
NM_213720.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHCHD10 | NM_213720.3 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | ENST00000484558.3 | |
CHCHD10 | NM_001301339.2 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | ||
CHCHD10 | NR_125755.2 | n.140-51G>T | intron_variant, non_coding_transcript_variant | ||||
CHCHD10 | NR_125756.2 | n.139+243G>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHCHD10 | ENST00000484558.3 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | 1 | NM_213720.3 | P1 | |
CHCHD10 | ENST00000401675.7 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | 5 | |||
CHCHD10 | ENST00000520222.1 | c.41+243G>T | intron_variant | 3 | |||||
CHCHD10 | ENST00000517886.1 | c.42-51G>T | intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 949590Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0AN XY: 465678
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Sep 14, 2022 | ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP1 - |
Lower motor neuron syndrome with late-adult onset;C4014648:Frontotemporal dementia and/or amyotrophic lateral sclerosis 2;C4015513:Autosomal dominant mitochondrial myopathy with exercise intolerance Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 15 of the CHCHD10 protein (p.Arg15Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 25113787, 25261972, 25681414, 25833818, 26152333, 30014597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180220). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects CHCHD10 function (PMID: 28585542, 29112723, 29121267, 29315381, 29789341). For these reasons, this variant has been classified as Pathogenic. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 01, 2015 | - - |
Autosomal dominant mitochondrial myopathy with exercise intolerance Other:1
not provided, no classification provided | literature only | GeneReviews | - | Variant observed to segregate with ALS (amyotrophic lateral sclerosis), in several families; likely responsible for less than 1 percent of familial ALS. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at