chr20-58389257-G-GCCTCGC

Position:

• chr20-58389257-G-GCCTCGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004738.5(VAPB):​c.-192_-187dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 670,770 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: VAPB NM_004738.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.441

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAPB	NM_004738.5	c.-192_-187dup		5_prime_UTR_variant	1/6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.-192_-187dup		5_prime_UTR_variant	1/3		NP_001182606.1
VAPB	NR_036633.2	n.40_45dup		non_coding_transcript_exon_variant	1/4
VAPB	XR_001754433.3	n.40_45dup		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.-192_-187dup		5_prime_UTR_variant	1/6	1	NM_004738.5	ENSP00000417175	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152024 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000362 AC: 42 AN: 115910 Hom.: 1 AF XY: 0.000390 AC XY: 25 AN XY: 64136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.000826

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000438

Gnomad OTH exome AF: 0.000851

GnomAD4 exome AF: 0.000507 AC: 263 AN: 518638 Hom.: 2 Cov.: 5 AF XY: 0.000642 AC XY: 181 AN XY: 281988

Gnomad4 AFR exome AF: 0.0000798

Gnomad4 AMR exome AF: 0.0000616

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.000156

Gnomad4 NFE exome AF: 0.000588

Gnomad4 OTH exome AF: 0.000496

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152132 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74364

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000397 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic Lateral Sclerosis, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spinal Muscular Atrophy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs765965868; hg19: chr20-56964313;