20-58389308-C-A
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_004738.5(VAPB):c.-152C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 708,918 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00040 ( 11 hom. )
Consequence
VAPB
NM_004738.5 5_prime_UTR
NM_004738.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0930
Genes affected
VAPB (HGNC:12649): (VAMP associated protein B and C) The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BS2
High AC in GnomAd4 at 52 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| VAPB | NM_004738.5 | c.-152C>A | 5_prime_UTR_variant | 1/6 | ENST00000475243.6 | ||
| VAPB | NM_001195677.2 | c.-152C>A | 5_prime_UTR_variant | 1/3 | |||
| VAPB | NR_036633.2 | n.80C>A | non_coding_transcript_exon_variant | 1/4 | |||
| VAPB | XR_001754433.3 | n.80C>A | non_coding_transcript_exon_variant | 1/6 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| VAPB | ENST00000475243.6 | c.-152C>A | 5_prime_UTR_variant | 1/6 | 1 | NM_004738.5 | P1 | ||
| VAPB | ENST00000395802.7 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes 0.000343 AC: 52AN: 151680Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000407 AC: 51AN: 125196Hom.: 1 AF XY: 0.000495 AC XY: 34AN XY: 68688
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GnomAD4 exome AF: 0.000398 AC: 222AN: 557130Hom.: 11 Cov.: 7 AF XY: 0.000412 AC XY: 123AN XY: 298550
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GnomAD4 genome 0.000343 AC: 52AN: 151788Hom.: 0 Cov.: 33 AF XY: 0.000431 AC XY: 32AN XY: 74210
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 8 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Adult-onset proximal spinal muscular atrophy, autosomal dominant Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at