11-66055218-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006842.3(SF3B2):c.401G>C(p.Arg134Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SF3B2
NM_006842.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Publications

0 publications found

Variant links:

Genes affected

SF3B2 (HGNC:10769): (splicing factor 3b subunit 2) This gene encodes subunit 2 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. Subunit 2 associates with pre-mRNA upstream of the branch site at the anchoring site. Subunit 2 also interacts directly with subunit 4 of the splicing factor 3b complex. Subunit 2 is a highly hydrophilic protein with a proline-rich N-terminus and a glutamate-rich stretch in the C-terminus. [provided by RefSeq, Jul 2008]

SF3B2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21962637).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B2	NM_006842.3 link	c.401G>C	p.Arg134Pro	missense_variant	Exon 4 of 22	ENST00000322535.11	NP_006833.2	Q13435
SF3B2	XM_005273726.5 link	c.401G>C	p.Arg134Pro	missense_variant	Exon 4 of 22		XP_005273783.1
SF3B2	XM_011544740.4 link	c.401G>C	p.Arg134Pro	missense_variant	Exon 4 of 22		XP_011543042.1
SF3B2	XM_017017144.3 link	c.401G>C	p.Arg134Pro	missense_variant	Exon 4 of 22		XP_016872633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B2	ENST00000322535.11 link	c.401G>C	p.Arg134Pro	missense_variant	Exon 4 of 22	1	NM_006842.3	ENSP00000318861.6		Q13435

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460386

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.000126

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111056

Other (OTH)

AF:

0.00

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 14, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;T;T;.;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Benign

0.0044

MetaRNN

Benign

0.22

T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.4

.;L;.;.;.;.

PhyloP100

1.3

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.44

N;N;N;D;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0030

D;D;D;D;D;.

Sift4G

Uncertain

0.025

D;D;T;T;T;T

Polyphen

0.98, 1.0

.;D;.;D;.;.

Vest4

0.33

MutPred

0.21

Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);.;.;

MVP

0.27

MPC

1.6

ClinPred

0.66

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.14

gMVP

0.19

Mutation Taster

=78/22

polymorphism

(source)

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

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11-66055218-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over