11-66052460-G-T

Position:

• chr11-66052460-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006842.3(SF3B2):​c.76G>T​(p.Ala26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00779 in 1,613,678 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (74 hom.)
• Consequence: SF3B2 NM_006842.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.06

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007796645).
• BP6: Variant 11-66052460-G-T is Benign according to our data. Variant chr11-66052460-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 770770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 937 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B2	NM_006842.3	c.76G>T	p.Ala26Ser	missense_variant	1/22	ENST00000322535.11
SF3B2	XM_005273726.5	c.76G>T	p.Ala26Ser	missense_variant	1/22
SF3B2	XM_011544740.4	c.76G>T	p.Ala26Ser	missense_variant	1/22
SF3B2	XM_017017144.3	c.76G>T	p.Ala26Ser	missense_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B2	ENST00000322535.11	c.76G>T	p.Ala26Ser	missense_variant	1/22	1	NM_006842.3	P1

Frequencies

GnomAD3 genomes AF: 0.00615 AC: 936 AN: 152228 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00732

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00945

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00657 AC: 1640 AN: 249662 Hom.: 20 AF XY: 0.00705 AC XY: 955 AN XY: 135536

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00952

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00796 AC: 11637 AN: 1461334 Hom.: 74 Cov.: 34 AF XY: 0.00802 AC XY: 5827 AN XY: 726968

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00890

Gnomad4 OTH exome AF: 0.00799

GnomAD4 genome AF: 0.00615 AC: 937 AN: 152344 Hom.: 5 Cov.: 32 AF XY: 0.00592 AC XY: 441 AN XY: 74504

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00731

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00947

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00950 Hom.: 6

Bravo AF: 0.00631

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00850 AC: 73

ExAC AF: 0.00660 AC: 801

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SF3B2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	May 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0078	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	.;N;.;.;.
MutationTaster	Benign	0.53	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.10	N;N;N;N;N
REVEL	Benign	0.053
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.10, 0.012	.;B;.;B;.
Vest4		0.33
MVP		0.46
MPC		0.41
ClinPred		0.044	T
GERP RS		4.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.21
gMVP		0.26

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: rs11554199; hg19: chr11-65819931; COSMIC: COSV99043782; COSMIC: COSV99043782;