2-197401887-C-T

Position:

chr2-197401887-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP3_ModeratePP5BS2_Supporting

The NM_012433.4(SF3B1):c.2225G>A(p.Gly742Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,587,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

SF3B1
NM_012433.4 missense, splice_region

Scores

Splicing: ADA: 0.09645

Clinical Significance

Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.85

Variant links:

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]

SF3B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.861

PP5

Variant 2-197401887-C-T is Pathogenic according to our data. Variant chr2-197401887-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376530.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SF3B1	NM_012433.4 linkuse as main transcript	c.2225G>A	p.Gly742Asp	missense_variant, splice_region_variant	16/25	ENST00000335508.11
SF3B1	XM_047443838.1 linkuse as main transcript	c.1787G>A	p.Gly596Asp	missense_variant, splice_region_variant	13/22
SF3B1	XM_047443839.1 linkuse as main transcript	c.1787G>A	p.Gly596Asp	missense_variant, splice_region_variant	13/22
SF3B1	XM_047443840.1 linkuse as main transcript	c.2225G>A	p.Gly742Asp	missense_variant, splice_region_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B1	ENST00000335508.11 linkuse as main transcript	c.2225G>A	p.Gly742Asp	missense_variant, splice_region_variant	16/25	1	NM_012433.4	P1	O75533-1
SF3B1	ENST00000470268.2 linkuse as main transcript	n.4109G>A		splice_region_variant, non_coding_transcript_exon_variant	15/24	2
SF3B1	ENST00000652026.1 linkuse as main transcript	c.*3292G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	16/25
SF3B1	ENST00000652738.1 linkuse as main transcript	c.*2484G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	17/26

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000348

AC:

AN:

1435806

Hom.:

Cov.:

AF XY:

0.00000420

AC XY:

AN XY:

713932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000453

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

B-cell chronic lymphocytic leukemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Papillary renal cell carcinoma type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.54

Sift

Benign

0.074

Sift4G

Benign

0.21

Polyphen

0.97

Vest4

0.87

MutPred

0.48

Loss of MoRF binding (P = 0.0452);

MVP

0.75

MPC

3.0

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.096

dbscSNV1_RF

Benign

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over