20-58389302-A-AC

Variant names:

• chr20-58389302-A-AC
• rs546898989
• NM_004738.5:c.-149dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004738.5(VAPB):​c.-149dupC 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
• Publications: 0 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 -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 Benign/Likely_benign. ClinVar VariationId 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.

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.-149dupC		5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.-149dupC		5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.83dupC		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.-149dupC		5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000903510.1		c.-149dupC		5_prime_UTR	Exon 1 of 7	ENSP00000573569.1
	VAPB	ENST00000903509.1		c.-149dupC		5_prime_UTR	Exon 1 of 5	ENSP00000573568.1

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

GnomAD2 exomes AF: 0.0601 AC: 4078 AN: 67844 AF XY: 0.0613

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 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

African (AFR) AF: 0.139 AC: 771 AN: 5552

American (AMR) AF: 0.0398 AC: 878 AN: 22088

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 593 AN: 9280

East Asian (EAS) AF: 0.00598 AC: 45 AN: 7522

South Asian (SAS) AF: 0.0589 AC: 3049 AN: 51764

European-Finnish (FIN) AF: 0.0352 AC: 590 AN: 16774

Middle Eastern (MID) AF: 0.0640 AC: 64 AN: 1000

European-Non Finnish (NFE) AF: 0.0779 AC: 10959 AN: 140718

Other (OTH) AF: 0.0750 AC: 920 AN: 12268

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

African (AFR) AF: 0.299 AC: 10425 AN: 34868

American (AMR) AF: 0.113 AC: 1496 AN: 13254

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 378 AN: 3104

East Asian (EAS) AF: 0.0155 AC: 63 AN: 4066

South Asian (SAS) AF: 0.0842 AC: 292 AN: 3468

European-Finnish (FIN) AF: 0.0536 AC: 394 AN: 7346

Middle Eastern (MID) AF: 0.0983 AC: 23 AN: 234

European-Non Finnish (NFE) AF: 0.101 AC: 6025 AN: 59520

Other (OTH) AF: 0.145 AC: 254 AN: 1748

Alfa AF: 0.0333 Hom.: 34

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)
-	-	1	not provided (1)
-	-	1	Spinal Muscular Atrophy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs546898989; hg19: chr20-56964358; COSMIC: COSV55666653; COSMIC: COSV55666653;