NM_006842.3:c.752C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006842.3(SF3B2):c.752C>T(p.Pro251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,521,712 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00098 ( 3 hom. )

Consequence

SF3B2
NM_006842.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

Publications

4 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:

ENSG00000255038 (HGNC:):

ENSG00000255038 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026429206).

BS2

High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B2	NM_006842.3 link	c.752C>T	p.Pro251Leu	missense_variant	Exon 7 of 22	ENST00000322535.11	NP_006833.2	Q13435
SF3B2	XM_005273726.5 link	c.749C>T	p.Pro250Leu	missense_variant	Exon 7 of 22		XP_005273783.1
SF3B2	XM_011544740.4 link	c.749C>T	p.Pro250Leu	missense_variant	Exon 7 of 22		XP_011543042.1
SF3B2	XM_017017144.3 link	c.746C>T	p.Pro249Leu	missense_variant	Exon 7 of 22		XP_016872633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B2	ENST00000322535.11 link	c.752C>T	p.Pro251Leu	missense_variant	Exon 7 of 22	1	NM_006842.3	ENSP00000318861.6		Q13435

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000594

AC:

148

AN:

249366

AF XY:

0.000678

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000976

AC:

1336

AN:

1369420

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

697

AN XY:

685712

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31898

American (AMR)

AF:

0.000112

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25554

East Asian (EAS)

AF:

0.00

AC:

AN:

39312

South Asian (SAS)

AF:

0.000343

AC:

AN:

84486

European-Finnish (FIN)

AF:

0.000207

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.000711

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00122

AC:

1256

AN:

1027488

Other (OTH)

AF:

0.000524

AC:

AN:

57226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000512

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41538

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000480

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.752C>T (p.P251L) alteration is located in exon 7 (coding exon 7) of the SF3B2 gene. This alteration results from a C to T substitution at nucleotide position 752, causing the proline (P) at amino acid position 251 to be replaced by a leucine (L). 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

Benign

0.15

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.067

T;T;T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.026

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

.;M;.;.;.

PhyloP100

3.2

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.9

D;D;D;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D

Polyphen

0.0030

.;B;.;.;.

Vest4

0.37

MVP

0.20

MPC

1.3

ClinPred

0.080

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Varity_R

0.17

gMVP

0.47

Mutation Taster

=93/7

polymorphism

(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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NM_006842.3:c.752C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over