20-58389302-A-AC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004738.5(VAPB):c.-149dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 395,364 control chromosomes in the GnomAD database, including 2,062 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1920 hom., cov: 27)
  • Exomes 𝑓: 0.067 (142 hom.)
• Consequence: VAPB NM_004738.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.452

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 20-58389302-A-AC is Benign according to our data. Variant chr20-58389302-A-AC is described in ClinVar as [Likely_benign]. Clinvar id is 338925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAPB	NM_004738.5	c.-149dup		5_prime_UTR_variant	1/6	ENST00000475243.6
VAPB	NM_001195677.2	c.-149dup		5_prime_UTR_variant	1/3
VAPB	NR_036633.2	n.83dup		non_coding_transcript_exon_variant	1/4
VAPB	XR_001754433.3	n.83dup		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAPB	ENST00000475243.6	c.-149dup		5_prime_UTR_variant	1/6	1	NM_004738.5	P1
VAPB	ENST00000395802.7			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 19399 AN: 128310 Hom.: 1919 Cov.: 27

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.0797

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0157

Gnomad SAS AF: 0.0847

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.0601 AC: 4078 AN: 67844 Hom.: 47 AF XY: 0.0613 AC XY: 2317 AN XY: 37796

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.0163

Gnomad SAS exome AF: 0.0488

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0737

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0669 AC: 17869 AN: 266966 Hom.: 142 Cov.: 5 AF XY: 0.0681 AC XY: 10352 AN XY: 151902

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0398

Gnomad4 ASJ exome AF: 0.0639

Gnomad4 EAS exome AF: 0.00598

Gnomad4 SAS exome AF: 0.0589

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0779

Gnomad4 OTH exome AF: 0.0750

GnomAD4 genome AF: 0.151 AC: 19413 AN: 128398 Hom.: 1920 Cov.: 27 AF XY: 0.148 AC XY: 9151 AN XY: 61718

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.0842

Gnomad4 FIN AF: 0.0536

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic Lateral Sclerosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2019

- -

Spinal Muscular Atrophy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs546898989; hg19: chr20-56964358;