rs1553177267
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePP3PP5_Moderate
The NM_003000.3(SDHB):c.756_765+4del variant causes a splice donor, splice donor region, coding sequence, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T252T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
SDHB
NM_003000.3 splice_donor, splice_donor_region, coding_sequence, intron
NM_003000.3 splice_donor, splice_donor_region, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.20
Genes affected
SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.07236062 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 1-17022603-CGTACCTTAGGACAG-C is Pathogenic according to our data. Variant chr1-17022603-CGTACCTTAGGACAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459171.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.756_765+4del | splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant | 7/8 | ENST00000375499.8 | ||
SDHB | NM_001407361.1 | c.702_711+4del | splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.756_765+4del | splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant | 7/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2018 | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency). This sequence change deletes 14 nucleotides from the exon/intron boundary of exon 7 of the SDHB gene, including nucleotides that affect the donor splice site in the last intron (intron 7). While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. A different variant affecting the donor splice site c.765+1G>A (also known as 899+1G>A) has been observed in an individual with malignant paraganglioma or pheochromocytoma (PMID: 15328326). In addition, truncations (p.Ile263Tyrfs*12, p.Ile263Serfs*13) that lie downstream of this variant have been determined to be likely pathogenic (Invitae). This suggests that disruption of this region of the SDHB protein is causative of disease. This variant has been observed in an individual with recurrent paragangliomas (Invitae). ClinVar contains an entry for this variant (Variation ID: 459171). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at