rs140920079
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_017841.4(SDHAF2):āc.476A>Cā(p.Glu159Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E159D) has been classified as Uncertain significance.
Frequency
Consequence
NM_017841.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHAF2 | NM_017841.4 | c.476A>C | p.Glu159Ala | missense_variant | 4/4 | ENST00000301761.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHAF2 | ENST00000301761.7 | c.476A>C | p.Glu159Ala | missense_variant | 4/4 | 1 | NM_017841.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251478Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727248
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74490
ClinVar
Submissions by phenotype
Paragangliomas 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 01, 2022 | The SDHAF2 c.476A>C (p.Glu159Ala) missense change has a maximum subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with SDHAF2-associated tumors. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 24, 2023 | To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00014 (5/35438 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2023 | 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 pheochromocytoma-paraganglioma Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces glutamic acid with alanine at codon 159 of the SDHAF2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 159 of the SDHAF2 protein (p.Glu159Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411605). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2024 | The p.E159A variant (also known as c.476A>C), located in coding exon 4 of the SDHAF2 gene, results from an A to C substitution at nucleotide position 476. The glutamic acid at codon 159 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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