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
Consequence
NM_005850.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at