1-149923657-C-CCAGTGTA

Position:

• chr1-149923657-C-CCAGTGTA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005850.5(SF3B4):​c.1159_1160insTACACTG​(p.Gly387ValfsTer101) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SF3B4 NM_005850.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.51

Genes affected

SF3B4 (HGNC:10771): (splicing factor 3b subunit 4) This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.091 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-149923657-C-CCAGTGTA is Pathogenic according to our data. Variant chr1-149923657-C-CCAGTGTA is described in ClinVar as [Pathogenic]. Clinvar id is 419756.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3B4	NM_005850.5	c.1159_1160insTACACTG	p.Gly387ValfsTer101	frameshift_variant	6/6	ENST00000271628.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3B4	ENST00000271628.9	c.1159_1160insTACACTG	p.Gly387ValfsTer101	frameshift_variant	6/6	1	NM_005850.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2015

The c.1153_1159dupTACACTG duplication in the SF3B4 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.1153_1159dupTACACTG duplication causes a frameshift starting with codon Glycine 387, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 101 of the new reading frame, denoted p.Gly389ValfsX101. This frameshift variant replaces the typical last 38 amino acid residues in the SF3B4 protein with 100 different amino acid residues, which is expected to alter the normal structure and function of the resultant protein. The c.1153_1159dupTACACTG duplication was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1153_1159dupTACACTG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553765608; hg19: chr1-149895549;