11-66057350-C-T

Position:

• chr11-66057350-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 13/20 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
SF3B2	NM_006842.3	c.752C>T	p.Pro251Leu	missense_variant	7/22	ENST00000322535.11
SF3B2	XM_005273726.5	c.749C>T	p.Pro250Leu	missense_variant	7/22
SF3B2	XM_011544740.4	c.749C>T	p.Pro250Leu	missense_variant	7/22
SF3B2	XM_017017144.3	c.746C>T	p.Pro249Leu	missense_variant	7/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B2	ENST00000322535.11	c.752C>T	p.Pro251Leu	missense_variant	7/22	1	NM_006842.3	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152174 Hom.: 0 Cov.: 31

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

GnomAD3 exomes AF: 0.000594 AC: 148 AN: 249366 Hom.: 0 AF XY: 0.000678 AC XY: 92 AN XY: 135630

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 SAS exome AF: 0.000392

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.: 3 Cov.: 26 AF XY: 0.00102 AC XY: 697 AN XY: 685712

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000343

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000524

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152292 Hom.: 0 Cov.: 31 AF XY: 0.000510 AC XY: 38 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.00125

EpiControl AF: 0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

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	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
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	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	.;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
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	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.17
gMVP		0.47

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: rs77713633; hg19: chr11-65824821; COSMIC: COSV105825993; COSMIC: COSV105825993;