Genetic Variant SF3B1:p.Tyr1295Cys (chr2-197392334-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012433.4(SF3B1):c.3884A>G(p.Tyr1295Cys) variant causes a missense change. 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SF3B1
NM_012433.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.74

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B1	NM_012433.4 link	c.3884A>G	p.Tyr1295Cys	missense_variant	Exon 25 of 25	ENST00000335508.11	NP_036565.2	O75533-1B4DGZ4
SF3B1	XM_047443838.1 link	c.3446A>G	p.Tyr1149Cys	missense_variant	Exon 22 of 22		XP_047299794.1
SF3B1	XM_047443839.1 link	c.3446A>G	p.Tyr1149Cys	missense_variant	Exon 22 of 22		XP_047299795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B1	ENST00000335508.11 link	c.3884A>G	p.Tyr1295Cys	missense_variant	Exon 25 of 25	1	NM_012433.4	ENSP00000335321.6		O75533-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1174276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

597976

African (AFR)

AF:

0.00

AC:

AN:

27752

American (AMR)

AF:

0.00

AC:

AN:

44008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24402

East Asian (EAS)

AF:

0.00

AC:

AN:

38394

South Asian (SAS)

AF:

0.00

AC:

AN:

80050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

850410

Other (OTH)

AF:

0.00

AC:

AN:

50758

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3884A>G (p.Y1295C) alteration is located in exon 25 (coding exon 25) of the SF3B1 gene. This alteration results from a A to G substitution at nucleotide position 3884, causing the tyrosine (Y) at amino acid position 1295 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.1

PhyloP100

3.7

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.017

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.85

MutPred

0.52

Gain of helix (P = 0.0425);

MVP

0.73

MPC

3.2

ClinPred

0.99

GERP RS

4.8

Varity_R

0.89

gMVP

0.96

Mutation Taster

=8/92

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over