2-197402109-T-G

Position:

• chr2-197402109-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_012433.4(SF3B1):​c.2099A>C​(p.Lys700Thr) variant causes a missense 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K700E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SF3B1 NM_012433.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.54

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a repeat HEAT 5 (size 38) in uniprot entity SF3B1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_012433.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-197402110-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376004.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 2-197402109-T-G is Pathogenic according to our data. Variant chr2-197402109-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376044.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B1	NM_012433.4	c.2099A>C	p.Lys700Thr	missense_variant	15/25	ENST00000335508.11
SF3B1	XM_047443838.1	c.1661A>C	p.Lys554Thr	missense_variant	12/22
SF3B1	XM_047443839.1	c.1661A>C	p.Lys554Thr	missense_variant	12/22
SF3B1	XM_047443840.1	c.2099A>C	p.Lys700Thr	missense_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11	c.2099A>C	p.Lys700Thr	missense_variant	15/25	1	NM_012433.4	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
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.55		Loss of ubiquitination at K700 (P = 0.0183);
MVP		0.66
MPC		2.8
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.8
Varity_R		0.88
gMVP		0.84

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: rs1057519756; hg19: chr2-198266833; COSMIC: COSV59225633; COSMIC: COSV59225633;