11-66055269-A-G

Position:

• chr11-66055269-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_006842.3(SF3B2):​c.452A>G​(p.Gln151Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SF3B2 NM_006842.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SF3B2
• BP4: Computational evidence support a benign effect (MetaRNN=0.27628517).
• BS2: High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B2	NM_006842.3	c.452A>G	p.Gln151Arg	missense_variant	4/22	ENST00000322535.11
SF3B2	XM_005273726.5	c.452A>G	p.Gln151Arg	missense_variant	4/22
SF3B2	XM_011544740.4	c.452A>G	p.Gln151Arg	missense_variant	4/22
SF3B2	XM_017017144.3	c.452A>G	p.Gln151Arg	missense_variant	4/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B2	ENST00000322535.11	c.452A>G	p.Gln151Arg	missense_variant	4/22	1	NM_006842.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250140 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461486 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727018

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

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

Jul 26, 2022

The c.452A>G (p.Q151R) alteration is located in exon 4 (coding exon 4) of the SF3B2 gene. This alteration results from a A to G substitution at nucleotide position 452, causing the glutamine (Q) at amino acid position 151 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	0.21
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T;T;T;.;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;T;D;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.96	N;N;D;D;N;D
REVEL	Benign	0.23
Sift	Uncertain	0.011	D;D;D;D;D;.
Sift4G	Uncertain	0.035	D;D;T;T;T;T
Polyphen		0.85, 0.97	.;P;.;D;.;.
Vest4		0.50
MutPred		0.17		Gain of MoRF binding (P = 0.0193);Gain of MoRF binding (P = 0.0193);Gain of MoRF binding (P = 0.0193);Gain of MoRF binding (P = 0.0193);.;.;
MVP		0.61
MPC		1.2
ClinPred		0.51	D
GERP RS		5.4
Varity_R		0.21
gMVP		0.42

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: rs1426111525; hg19: chr11-65822740;