rs111402137
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_017841.4(SDHAF2):āc.139A>Gā(p.Met47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. M47L) has been classified as Uncertain significance.
Frequency
Consequence
NM_017841.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHAF2 | NM_017841.4 | c.139A>G | p.Met47Val | missense_variant | 2/4 | ENST00000301761.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHAF2 | ENST00000301761.7 | c.139A>G | p.Met47Val | missense_variant | 2/4 | 1 | NM_017841.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251416Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135864
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727228
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152374Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74512
ClinVar
Submissions by phenotype
Hereditary pheochromocytoma-paraganglioma Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the SDHAF2 protein (p.Met47Val). This variant is present in population databases (rs111402137, gnomAD 0.009%). This missense change has been observed in individual(s) with phaeochromocytoma (PMID: 20071235). ClinVar contains an entry for this variant (Variation ID: 486407). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. - |
Paragangliomas 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 19, 2023 | The frequency of this variant in the general population, 0.000028 (8/282814 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in one individual with phaeochromocytoma (PMID: 20071235 (2010)), and in a family clinically suspicious of hereditary breast/ovarian cancer (PMID: 30306255 (2018)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 25, 2024 | The p.M47V variant (also known as c.139A>G), located in coding exon 2 of the SDHAF2 gene, results from an A to G substitution at nucleotide position 139. The methionine at codon 47 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in 1/443 patients with apparently sporadic paragangliomas or pheochromocytomas and 0/200 healthy blood donors; however, authors of this study concluded that this alteration was non-pathogenic (Bayley JP et al. Lancet Oncol. 2010 Apr;11:366-72). This alteration was also identified in a Spanish family suspicious of hereditary breast and/or ovarian cancer syndrome (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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