rs770506764
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004168.4(SDHA):c.1429C>T(p.Pro477Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1429C>T | p.Pro477Ser | missense_variant | Exon 10 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1429C>T | p.Pro477Ser | missense_variant | Exon 10 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*162C>T | non_coding_transcript_exon_variant | Exon 9 of 24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*162C>T | 3_prime_UTR_variant | Exon 9 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251156Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135734
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461492Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727074
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
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Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
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Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 477 of the SDHA protein (p.Pro477Ser). This variant is present in population databases (rs770506764, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 412339). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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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Hereditary cancer-predisposing syndrome Uncertain:1
The p.P477S variant (also known as c.1429C>T), located in coding exon 10 of the SDHA gene, results from a C to T substitution at nucleotide position 1429. The proline at codon 477 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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