chr11-66055140-C-G

Variant names:

• chr11-66055140-C-G
• NM_006842.3:c.323C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006842.3(SF3B2):​c.323C>G​(p.Pro108Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SF3B2 NM_006842.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24259827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B2	NM_006842.3	c.323C>G	p.Pro108Arg	missense_variant	Exon 4 of 22	ENST00000322535.11	NP_006833.2
SF3B2	XM_005273726.5	c.323C>G	p.Pro108Arg	missense_variant	Exon 4 of 22		XP_005273783.1
SF3B2	XM_011544740.4	c.323C>G	p.Pro108Arg	missense_variant	Exon 4 of 22		XP_011543042.1
SF3B2	XM_017017144.3	c.323C>G	p.Pro108Arg	missense_variant	Exon 4 of 22		XP_016872633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B2	ENST00000322535.11	c.323C>G	p.Pro108Arg	missense_variant	Exon 4 of 22	1	NM_006842.3	ENSP00000318861.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323C>G (p.P108R) alteration is located in exon 4 (coding exon 4) of the SF3B2 gene. This alteration results from a C to G substitution at nucleotide position 323, causing the proline (P) at amino acid position 108 to be replaced by an arginine (R). 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	0.24
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.017	T;T;T;.;.;T
Eigen	Benign	0.090
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.1	.;L;.;.;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.0	N;N;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.010	D;D;T;D;T;.
Sift4G	Benign	0.096	T;T;D;T;T;D
Polyphen		0.97, 0.99	.;D;.;D;.;.
Vest4		0.45
MutPred		0.27		Loss of glycosylation at P108 (P = 3e-04);Loss of glycosylation at P108 (P = 3e-04);Loss of glycosylation at P108 (P = 3e-04);Loss of glycosylation at P108 (P = 3e-04);.;.;
MVP		0.75
MPC		1.3
ClinPred		0.48	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.065
gMVP		0.31
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr11-65822611;