11-66057366-G-T

Position:

• chr11-66057366-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006842.3(SF3B2):​c.768G>T​(p.Glu256Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SF3B2 NM_006842.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.392

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SF3B2
• BP4: Computational evidence support a benign effect (MetaRNN=0.054674685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B2	NM_006842.3	c.768G>T	p.Glu256Asp	missense_variant	7/22	ENST00000322535.11
SF3B2	XM_005273726.5	c.765G>T	p.Glu255Asp	missense_variant	7/22
SF3B2	XM_011544740.4	c.765G>T	p.Glu255Asp	missense_variant	7/22
SF3B2	XM_017017144.3	c.762G>T	p.Glu254Asp	missense_variant	7/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B2	ENST00000322535.11	c.768G>T	p.Glu256Asp	missense_variant	7/22	1	NM_006842.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1223234 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 619172

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SF3B2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2023

The SF3B2 c.768G>T variant is predicted to result in the amino acid substitution p.Glu256Asp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In multiple species an aspartic acid (Asp) is seen at the Glu256 residue. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0060	T;T;T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.055	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.55	N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.51	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0020	.;B;.;.;.
Vest4		0.14
MutPred		0.32		.;Loss of catalytic residue at E256 (P = 0.1448);.;.;.;
MVP		0.082
MPC		0.41
ClinPred		0.20	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.064
gMVP		0.055

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: rs1857019745; hg19: chr11-65824837;