rs749824479
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004168.4(SDHA):c.464A>G(p.Asn155Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,704 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.464A>G | p.Asn155Ser | missense_variant | Exon 5 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.464A>G | p.Asn155Ser | missense_variant | Exon 5 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.464A>G | non_coding_transcript_exon_variant | Exon 5 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251098Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135822
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460520Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 726616
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74342
ClinVar
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 155 of the SDHA protein (p.Asn155Ser). This variant is present in population databases (rs749824479, 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: 472393). 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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not provided Uncertain:1
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; 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.; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.N155S variant (also known as c.464A>G), located in coding exon 5 of the SDHA gene, results from an A to G substitution at nucleotide position 464. The asparagine at codon 155 is replaced by serine, 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