20-58389302-AC-ACCC

Variant names:

• chr20-58389302-A-ACC
• rs546898989
• NM_004738.5:c.-150_-149dupCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004738.5(VAPB):​c.-150_-149dupCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 396,280 control chromosomes in the GnomAD database, including 272 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (231 hom., cov: 27)
  • Exomes 𝑓: 0.028 (41 hom.)
• Consequence: VAPB NM_004738.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 20-58389302-A-ACC is Benign according to our data. Variant chr20-58389302-A-ACC is described in ClinVar as Benign. ClinVar VariationId is 1297397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0798 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.-150_-149dupCC		5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.-150_-149dupCC		5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.82_83dupCC		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.-150_-149dupCC		5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000903510.1		c.-150_-149dupCC		5_prime_UTR	Exon 1 of 7	ENSP00000573569.1
	VAPB	ENST00000903509.1		c.-150_-149dupCC		5_prime_UTR	Exon 1 of 5	ENSP00000573568.1

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 7195 AN: 128258 Hom.: 231 Cov.: 27

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0287

Gnomad EAS AF: 0.00123

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0200

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0341

GnomAD2 exomes AF: 0.00886 AC: 601 AN: 67844 AF XY: 0.00841

Gnomad AFR exome AF: 0.00619

Gnomad AMR exome AF: 0.00661

Gnomad ASJ exome AF: 0.00777

Gnomad EAS exome AF: 0.000403

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00982

GnomAD4 exome AF: 0.0284 AC: 7605 AN: 267936 Hom.: 41 Cov.: 5 AF XY: 0.0277 AC XY: 4234 AN XY: 152676

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00836 AC: 47 AN: 5624

American (AMR) AF: 0.00524 AC: 117 AN: 22348

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 99 AN: 9400

East Asian (EAS) AF: 0.000132 AC: 1 AN: 7562

South Asian (SAS) AF: 0.00726 AC: 381 AN: 52484

European-Finnish (FIN) AF: 0.0505 AC: 840 AN: 16648

Middle Eastern (MID) AF: 0.00585 AC: 6 AN: 1026

European-Non Finnish (NFE) AF: 0.0410 AC: 5764 AN: 140498

Other (OTH) AF: 0.0283 AC: 350 AN: 12346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0560 AC: 7191 AN: 128344 Hom.: 231 Cov.: 27 AF XY: 0.0561 AC XY: 3456 AN XY: 61654

African (AFR) AF: 0.0193 AC: 675 AN: 34948

American (AMR) AF: 0.0241 AC: 319 AN: 13248

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 89 AN: 3104

East Asian (EAS) AF: 0.000984 AC: 4 AN: 4066

South Asian (SAS) AF: 0.0156 AC: 54 AN: 3468

European-Finnish (FIN) AF: 0.141 AC: 1028 AN: 7280

Middle Eastern (MID) AF: 0.0214 AC: 5 AN: 234

European-Non Finnish (NFE) AF: 0.0818 AC: 4861 AN: 59454

Other (OTH) AF: 0.0337 AC: 59 AN: 1750

Alfa AF: 0.0275 Hom.: 34

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

Other links and lift over

dbSNP: rs546898989; hg19: chr20-56964358;