20-58419347-T-G

Variant names:

• chr20-58419347-T-G
• rs6026256
• NM_004738.5:c.211+984T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004738.5(VAPB):​c.211+984T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 151,942 control chromosomes in the GnomAD database, including 6,150 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6150 hom., cov: 32)
• Consequence: VAPB NM_004738.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004738.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	NM_004738.5	MANE Select	c.211+984T>G		intron	N/A	NP_004729.1
	VAPB	NM_001195677.2		c.211+984T>G		intron	N/A	NP_001182606.1
	VAPB	NR_036633.2		n.442+984T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.211+984T>G		intron	N/A	ENSP00000417175.1
	VAPB	ENST00000395802.7	TSL:1	c.211+984T>G		intron	N/A	ENSP00000379147.3
	VAPB	ENST00000903510.1		c.271+984T>G		intron	N/A	ENSP00000573569.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42338 AN: 151824 Hom.: 6147 Cov.: 32

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.279 AC: 42356 AN: 151942 Hom.: 6150 Cov.: 32 AF XY: 0.282 AC XY: 20960 AN XY: 74270

African (AFR) AF: 0.337 AC: 13940 AN: 41396

American (AMR) AF: 0.189 AC: 2885 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3472

East Asian (EAS) AF: 0.321 AC: 1661 AN: 5170

South Asian (SAS) AF: 0.313 AC: 1506 AN: 4812

European-Finnish (FIN) AF: 0.323 AC: 3402 AN: 10542

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16941 AN: 67950

Other (OTH) AF: 0.260 AC: 550 AN: 2112

Alfa AF: 0.152 Hom.: 285

Bravo AF: 0.267

Asia WGS AF: 0.314 AC: 1090 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.2
DANN	Benign	0.49
PhyloP100		-0.23
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: rs6026256; hg19: chr20-56994403;