rs587777466
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000437048.7(VPS53):c.1556+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
ENST00000437048.7 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS53 | NM_001128159.3 | c.1556+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000437048.7 | NP_001121631.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS53 | ENST00000437048.7 | c.1556+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_001128159.3 | ENSP00000401435 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152010Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461836Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727212
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152010Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74230
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 2E Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 12, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2023 | This sequence change falls in intron 14 of the VPS53 gene. It does not directly change the encoded amino acid sequence of the VPS53 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with progressive cerebello-cerebral atrophy (PMID: 24577744, 30100179). It is commonly reported in individuals of Moroccan Jewish ancestry (PMID: 24577744, 30100179). ClinVar contains an entry for this variant (Variation ID: 139445). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pontoneocerebellar hypoplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2022 | Variant summary: VPS53 c.1556+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict it weakens a 5' donor site. Experimental evidence supports these predictions indicating the variant generates an aberrant/unstable transcript (Feinstein_2014). The variant was absent in 251280 control chromosomes (gnomAD). c.1556+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Pontocerebellar Hypoplasia, Type 2E (example, Feinstein_2014 and Hady-Cohen_2018). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at