11-66057322-C-T

Position:

• chr11-66057322-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006842.3(SF3B2):​c.724C>T​(p.Pro242Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,868 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SF3B2 NM_006842.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11298594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SF3B2	NM_006842.3	c.724C>T	p.Pro242Ser	missense_variant	7/22	ENST00000322535.11	NP_006833.2
SF3B2	XM_005273726.5	c.721C>T	p.Pro241Ser	missense_variant	7/22		XP_005273783.1
SF3B2	XM_011544740.4	c.721C>T	p.Pro241Ser	missense_variant	7/22		XP_011543042.1
SF3B2	XM_017017144.3	c.718C>T	p.Pro240Ser	missense_variant	7/22		XP_016872633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SF3B2	ENST00000322535.11	c.724C>T	p.Pro242Ser	missense_variant	7/22	1	NM_006842.3	ENSP00000318861	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456868 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725144

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jan 29, 2024

The c.724C>T (p.P242S) 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 724, causing the proline (P) at amino acid position 242 to be replaced by a serine (S). 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	0.065
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.86	D;D;D;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	.;L;.;.;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.041
Sift	Benign	0.15	T;T;D;T;T
Sift4G	Benign	0.39	T;T;D;T;T
Polyphen		0.033	.;B;.;.;.
Vest4		0.47
MutPred		0.22		.;Gain of phosphorylation at P242 (P = 0.0081);.;.;.;
MVP		0.13
MPC		0.46
ClinPred		0.47	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.043
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-65824793;