rs148425779
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_017841.4(SDHAF2):c.32C>A(p.Ser11Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Likely benign.
Frequency
Consequence
NM_017841.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHAF2 | NM_017841.4 | c.32C>A | p.Ser11Ter | stop_gained | 1/4 | ENST00000301761.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHAF2 | ENST00000301761.7 | c.32C>A | p.Ser11Ter | stop_gained | 1/4 | 1 | NM_017841.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727222
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser11*) in the SDHAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHAF2 are known to be pathogenic (PMID: 22241717, 26096992). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2023 | The p.S11* variant (also known as c.32C>A), located in coding exon 1 of the SDHAF2 gene, results from a C to A substitution at nucleotide position 32. This changes the amino acid from a serine to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theSDHAF2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown. 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