20-58442455-C-T

Variant names:

• chr20-58442455-C-T
• rs6100067
• NM_004738.5:c.573+1372C>T

Variant summary

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

The NM_004738.5(VAPB):​c.573+1372C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 151,848 control chromosomes in the GnomAD database, including 8,956 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 0.34 (8956 hom., cov: 32)
• Consequence: VAPB NM_004738.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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=-0.62).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.351 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.573+1372C>T		intron	N/A	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.212-1622C>T		intron	N/A	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.619+1372C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.573+1372C>T		intron	N/A	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.212-1622C>T		intron	N/A	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.633+1372C>T		intron	N/A	ENSP00000573569.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51148 AN: 151732 Hom.: 8953 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.337 AC: 51168 AN: 151848 Hom.: 8956 Cov.: 32 AF XY: 0.343 AC XY: 25422 AN XY: 74190

African (AFR) AF: 0.356 AC: 14735 AN: 41370

American (AMR) AF: 0.210 AC: 3208 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3468

East Asian (EAS) AF: 0.324 AC: 1672 AN: 5168

South Asian (SAS) AF: 0.329 AC: 1575 AN: 4794

European-Finnish (FIN) AF: 0.476 AC: 5018 AN: 10532

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22679 AN: 67934

Other (OTH) AF: 0.292 AC: 616 AN: 2108

Alfa AF: 0.333 Hom.: 3990

Bravo AF: 0.312

Asia WGS AF: 0.325 AC: 1130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		0.42
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: rs6100067; hg19: chr20-57017511;