11-66057328-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_006842.3(SF3B2):c.730C>G(p.Pro244Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,605,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: SF3B2 NM_006842.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SF3B2
• BP4: Computational evidence support a benign effect (MetaRNN=0.12541696).
• BP6: Variant 11-66057328-C-G is Benign according to our data. Variant chr11-66057328-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3160822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B2	NM_006842.3	c.730C>G	p.Pro244Ala	missense_variant	7/22	ENST00000322535.11
SF3B2	XM_005273726.5	c.727C>G	p.Pro243Ala	missense_variant	7/22
SF3B2	XM_011544740.4	c.727C>G	p.Pro243Ala	missense_variant	7/22
SF3B2	XM_017017144.3	c.724C>G	p.Pro242Ala	missense_variant	7/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B2	ENST00000322535.11	c.730C>G	p.Pro244Ala	missense_variant	7/22	1	NM_006842.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000180 AC: 45 AN: 249894 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000283 AC: 412 AN: 1453540 Hom.: 0 Cov.: 29 AF XY: 0.000289 AC XY: 209 AN XY: 723664

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000447

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: 0.000353

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T;T;T;.;.
Eigen	Benign	0.0036
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.87	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N;N;D;D;D
REVEL	Benign	0.032
Sift	Benign	0.046	D;T;T;T;T
Sift4G	Uncertain	0.021	D;D;D;D;D
Polyphen		0.30	.;B;.;.;.
Vest4		0.28
MVP		0.32
MPC		0.44
ClinPred		0.070	T
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.031
gMVP		0.14

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: rs201649157; hg19: chr11-65824799;