11-66052385-A-T

Variant names:

• chr11-66052385-A-T
• rs2135031513
• NM_006842.3:c.1A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_006842.3(SF3B2):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SF3B2 NM_006842.3 initiator_codon
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.82
• 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 5 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 83 codons. Genomic position: 66053093. Lost 0.092 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-66052385-A-T is Pathogenic according to our data. Variant chr11-66052385-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1342663.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SF3B2	NM_006842.3	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 22	ENST00000322535.11	NP_006833.2
SF3B2	XM_005273726.5	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 22		XP_005273783.1
SF3B2	XM_011544740.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 22		XP_011543042.1
SF3B2	XM_017017144.3	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 22		XP_016872633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SF3B2	ENST00000322535.11	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 22	1	NM_006842.3	ENSP00000318861.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Craniofacial microsomia 1 Pathogenic:1

Jul 13, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.011	T;T;T;.
Eigen	Benign	-0.019
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.60	T
PhyloP100		3.8
PROVEAN	Benign	-0.79	N;N;N;N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.064	.;B;.;B
Vest4		0.80
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.0553);Loss of catalytic residue at M1 (P = 0.0553);Loss of catalytic residue at M1 (P = 0.0553);Loss of catalytic residue at M1 (P = 0.0553);
MVP		0.87
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.62	Under-expression
Varity_R		0.96
gMVP		0.67
Mutation Taster		=9/191	disease causing

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

Other links and lift over

dbSNP: rs2135031513; hg19: chr11-65819856;