rs749527870
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_017841.4(SDHAF2):c.260+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_017841.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHAF2 | NM_017841.4 | c.260+1G>A | splice_donor_variant | ENST00000301761.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHAF2 | ENST00000301761.7 | c.260+1G>A | splice_donor_variant | 1 | NM_017841.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460222Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726434
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary pheochromocytoma-paraganglioma Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 07, 2023 | The c.260+1G>A variant of the SDHAF2 gene is predicted to disrupt mRNA splicing (spliceAI 0.96), affecting the donor splice site in intron 2 and resulting in an absent or aberrant protein product. Loss-of-function variants in SDHAF2 gene are known to be pathogenic (PMID: 22241717, 31687641, 26096992). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. This variant has a very low frequency (1/248010) in the general population according to gnomAD. For these reasons, the c.260+1G>A variant in the SDHAF2 gene has been classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change affects a donor splice site in intron 2 of the SDHAF2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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: 463821). Studies have shown that disruption of this splice site results in skipping of exon 2 and exons 2-3 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2023 | The c.260+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the SDHAF2 gene. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at