5-225530-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_004168.4(SDHA):c.424A>G(p.Met142Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.424A>G | p.Met142Val | missense_variant | Exon 4 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.424A>G | p.Met142Val | missense_variant | Exon 4 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.424A>G | non_coding_transcript_exon_variant | Exon 4 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250558Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135594
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461640Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727126
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
The p.Met142Val variant in the SDHAgene has not been previously reported in association with disease.•This variant has been identified in 4/24,758 African/African-American chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency.•Computational tools predict that this variant is deleterious; however, the accuracy of in silicoalgorithms is limited.•These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Met142Val variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP3] -
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 methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 142 of the SDHA protein (p.Met142Val). This variant is present in population databases (rs776848209, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SDHA-related conditions (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 412352). 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. -
not provided Uncertain:1
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 -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.M142V variant (also known as c.424A>G), located in coding exon 4 of the SDHA gene, results from an A to G substitution at nucleotide position 424. The methionine at codon 142 is replaced by valine, 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at