rs2234489

Variant names:

• chr20-58438817-G-A
• rs2234489
• NM_004738.5:c.316-128G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58438817-G-A
• chr20-58438817-G-C
• chr20-58438817-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004738.5(VAPB):​c.316-128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 750,374 control chromosomes in the GnomAD database, including 12,771 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2680 hom., cov: 32)
  • Exomes 𝑓: 0.17 (10091 hom.)
• Consequence: VAPB NM_004738.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.27
• Publications: 5 publications found

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]

VAPB Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• adult-onset proximal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 20-58438817-G-A is Benign according to our data. Variant chr20-58438817-G-A is described in ClinVar as Benign. ClinVar VariationId is 1181952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.316-128G>A		intron_variant	Intron 3 of 5	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.212-5260G>A		intron_variant	Intron 2 of 2		NP_001182606.1
VAPB	NR_036633.2	n.443-2090G>A		intron_variant	Intron 2 of 3
VAPB	XR_001754433.3	n.547-128G>A		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.316-128G>A		intron_variant	Intron 3 of 5	1	NM_004738.5	ENSP00000417175.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27189 AN: 152058 Hom.: 2675 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0915

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.169 AC: 101301 AN: 598198 Hom.: 10091 AF XY: 0.174 AC XY: 55473 AN XY: 319480

African (AFR) AF: 0.228 AC: 3412 AN: 14954

American (AMR) AF: 0.0641 AC: 1758 AN: 27408

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 3147 AN: 18584

East Asian (EAS) AF: 0.348 AC: 11196 AN: 32184

South Asian (SAS) AF: 0.249 AC: 14345 AN: 57608

European-Finnish (FIN) AF: 0.258 AC: 9129 AN: 35430

Middle Eastern (MID) AF: 0.160 AC: 385 AN: 2404

European-Non Finnish (NFE) AF: 0.140 AC: 53068 AN: 378316

Other (OTH) AF: 0.155 AC: 4861 AN: 31310

GnomAD4 genome AF: 0.179 AC: 27210 AN: 152176 Hom.: 2680 Cov.: 32 AF XY: 0.186 AC XY: 13838 AN XY: 74396

African (AFR) AF: 0.227 AC: 9428 AN: 41496

American (AMR) AF: 0.0912 AC: 1395 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3470

East Asian (EAS) AF: 0.310 AC: 1608 AN: 5180

South Asian (SAS) AF: 0.254 AC: 1224 AN: 4820

European-Finnish (FIN) AF: 0.274 AC: 2898 AN: 10576

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9547 AN: 68020

Other (OTH) AF: 0.153 AC: 323 AN: 2112

Alfa AF: 0.135 Hom.: 1315

Bravo AF: 0.164

Asia WGS AF: 0.264 AC: 916 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.45
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2234489; hg19: chr20-57013873;