2-197400846-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_012433.4(SF3B1):c.2587C>T(p.Gln863Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
SF3B1
NM_012433.4 stop_gained
NM_012433.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.84
Genes affected
SF3B1 (HGNC:10768): (splicing factor 3b subunit 1) This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeats that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SF3B1 | NM_012433.4 | c.2587C>T | p.Gln863Ter | stop_gained | 18/25 | ENST00000335508.11 | |
SF3B1 | XM_047443838.1 | c.2149C>T | p.Gln717Ter | stop_gained | 15/22 | ||
SF3B1 | XM_047443839.1 | c.2149C>T | p.Gln717Ter | stop_gained | 15/22 | ||
SF3B1 | XM_047443840.1 | c.2587C>T | p.Gln863Ter | stop_gained | 18/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SF3B1 | ENST00000335508.11 | c.2587C>T | p.Gln863Ter | stop_gained | 18/25 | 1 | NM_012433.4 | P1 | |
SF3B1 | ENST00000470268.2 | n.4471C>T | non_coding_transcript_exon_variant | 17/24 | 2 | ||||
SF3B1 | ENST00000652026.1 | c.*3654C>T | 3_prime_UTR_variant, NMD_transcript_variant | 18/25 | |||||
SF3B1 | ENST00000652738.1 | c.*2846C>T | 3_prime_UTR_variant, NMD_transcript_variant | 19/26 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2021 | Variant summary: SF3B1 c.2587C>T (p.Gln863X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant was absent in 250938 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2587C>T in individuals affected with SF3B1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. In addition, though animal models noted various skeletal phenotypic outcomes and reduced number of hematopoietic stem cells in SF3B1 haploinsufficient mice (PMID: 15741318, 24535406), to our knowledge no truncating SF3B1 variants have been reported in affected individuals in the germline state (HGMD, ClinVar). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at