chr11-66055572-A-G

Variant names:

• chr11-66055572-A-G
• NM_006842.3:c.536A>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.536A>G​(p.Glu179Gly) 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. 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: 2.42
• 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=0.12304565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B2	NM_006842.3	c.536A>G	p.Glu179Gly	missense_variant	Exon 5 of 22	ENST00000322535.11	NP_006833.2
SF3B2	XM_005273726.5	c.536A>G	p.Glu179Gly	missense_variant	Exon 5 of 22		XP_005273783.1
SF3B2	XM_011544740.4	c.533A>G	p.Glu178Gly	missense_variant	Exon 5 of 22		XP_011543042.1
SF3B2	XM_017017144.3	c.533A>G	p.Glu178Gly	missense_variant	Exon 5 of 22		XP_016872633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B2	ENST00000322535.11	c.536A>G	p.Glu179Gly	missense_variant	Exon 5 of 22	1	NM_006842.3	ENSP00000318861.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Apr 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536A>G (p.E179G) alteration is located in exon 5 (coding exon 5) of the SF3B2 gene. This alteration results from a A to G substitution at nucleotide position 536, causing the glutamic acid (E) at amino acid position 179 to be replaced by a glycine (G). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	N;D;D;D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.030	D;T;D;D
Polyphen		0.0	B;.;B;.
Vest4		0.36
MutPred		0.16		Loss of helix (P = 0.0304);.;.;.;
MVP		0.12
MPC		0.54
ClinPred		0.42	T
GERP RS		1.9
Varity_R		0.25
gMVP		0.49
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr11-65823043;