rs559063155

Positions:

• chr2-197402110-T-A
• chr2-197402110-T-C
• chr2-197402110-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_012433.4(SF3B1):​c.2098A>T​(p.Lys700Ter) 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 Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SF3B1 NM_012433.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.51

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 11 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
• PP5: Variant 2-197402110-T-A is Pathogenic according to our data. Variant chr2-197402110-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376045.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SF3B1	NM_012433.4	c.2098A>T	p.Lys700Ter	stop_gained	15/25	ENST00000335508.11	NP_036565.2
SF3B1	XM_047443838.1	c.1660A>T	p.Lys554Ter	stop_gained	12/22		XP_047299794.1
SF3B1	XM_047443839.1	c.1660A>T	p.Lys554Ter	stop_gained	12/22		XP_047299795.1
SF3B1	XM_047443840.1	c.2098A>T	p.Lys700Ter	stop_gained	15/22		XP_047299796.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SF3B1	ENST00000335508.11	c.2098A>T	p.Lys700Ter	stop_gained	15/25	1	NM_012433.4	ENSP00000335321	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.98
GERP RS		6.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs559063155; hg19: chr2-198266834;