2-197400846-G-A

Position:

• chr2-197400846-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Aug 05, 2024

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. However, to our knowledge, Loss of function is not an established mechanism for SF3B1 related diseases. 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).ClinVar contains an entry for this variant (Variation ID: 917660). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2084930929; hg19: chr2-198265570;