rs376986935
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_004168.4(SDHA):c.1936G>A(p.Asp646Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1936G>A | p.Asp646Asn | missense_variant | Exon 15 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1936G>A | p.Asp646Asn | missense_variant | Exon 15 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*669G>A | non_coding_transcript_exon_variant | Exon 14 of 24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*669G>A | 3_prime_UTR_variant | Exon 14 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251182Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135744
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461532Hom.: 1 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727106
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74352
ClinVar
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 646 of the SDHA protein (p.Asp646Asn). This variant is present in population databases (rs376986935, gnomAD 0.006%). This missense change has been observed in individual(s) with SDHA-related conditions (PMID: 38127826). ClinVar contains an entry for this variant (Variation ID: 566572). 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 SDHA protein function with a negative 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. -
Dilated cardiomyopathy 1GG Uncertain:1
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.D646N variant (also known as c.1936G>A), located in coding exon 15 of the SDHA gene, results from a G to A substitution at nucleotide position 1936. The aspartic acid at codon 646 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at