1-17053948-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6
The NM_003000.3(SDHB):c.72G>A(p.Gln24=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000685 in 1,459,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SDHB
NM_003000.3 splice_region, synonymous
NM_003000.3 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9927
2
Clinical Significance
Conservation
PhyloP100: 3.92
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BP6
Variant 1-17053948-C-T is Benign according to our data. Variant chr1-17053948-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528740.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SDHB | NM_003000.3 | c.72G>A | p.Gln24= | splice_region_variant, synonymous_variant | 1/8 | ENST00000375499.8 | |
| SDHB | NM_001407361.1 | c.72G>A | p.Gln24= | splice_region_variant, synonymous_variant | 1/8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SDHB | ENST00000375499.8 | c.72G>A | p.Gln24= | splice_region_variant, synonymous_variant | 1/8 | 1 | NM_003000.3 | P1 | |
| SDHB | ENST00000466613.2 | n.84G>A | splice_region_variant, non_coding_transcript_exon_variant | 1/3 | 2 | ||||
| SDHB | ENST00000485515.5 | n.60G>A | splice_region_variant, non_coding_transcript_exon_variant | 1/7 | 5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459928Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726184
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30
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GnomAD4 genome
GnomAD4 genome
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31
Bravo
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2022 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 528740). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 24 of the SDHB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SDHB protein. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. - |
Hereditary pheochromocytoma-paraganglioma Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at