1-149923657-C-CCAGTGTA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_005850.5(SF3B4):​c.1153_1159dupTACACTG​(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.51
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SF3B4NM_005850.5 linkc.1153_1159dupTACACTG p.Gly387ValfsTer101 frameshift_variant Exon 6 of 6 ENST00000271628.9 NP_005841.1 Q15427B3KUJ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SF3B4ENST00000271628.9 linkc.1153_1159dupTACACTG p.Gly387ValfsTer101 frameshift_variant Exon 6 of 6 1 NM_005850.5 ENSP00000271628.8 Q15427

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Dec 18, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1153_1159dupTACACTG (p.G387Vfs*101) alteration, located in exon 6 (coding exon 6) of the SF3B4 gene, consists of a duplication of TACACTG at position 1153, causing a translational frameshift with a predicted alternate stop codon after 101 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). This frameshift impacts the last 9% of the native protein and results in the elongation of the protein by 63 amino acids. The exact functional impact of these altered amino acids is unknown at this time. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was determined to be de novo in at least one individual with features consistent with SF3B4-related Nager acrofacial dysostosis (external communication). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1
Aug 17, 2015
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553765608; hg19: chr1-149895549; API