rs546898989

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-58389302-AC-A
• chr20-58389302-AC-ACC
• chr20-58389302-AC-ACCC
• chr20-58389302-AC-ACCCC
• chr20-58389302-AC-ACCCCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004738.5(VAPB):​c.-149delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 390,658 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0042 (1 hom.)
• Consequence: VAPB NM_004738.5 5_prime_UTR
• Clinical Significance: Likely 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 20-58389302-AC-A is Benign according to our data. Variant chr20-58389302-AC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1195499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 71 AD gene.

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.-149delC		5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.-149delC		5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.83delC		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.-149delC		5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000903510.1		c.-149delC		5_prime_UTR	Exon 1 of 7	ENSP00000573569.1
	VAPB	ENST00000903509.1		c.-149delC		5_prime_UTR	Exon 1 of 5	ENSP00000573568.1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 70 AN: 128488 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000377

Gnomad ASJ AF: 0.000322

Gnomad EAS AF: 0.000490

Gnomad SAS AF: 0.000288

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000577

GnomAD2 exomes AF: 0.00958 AC: 650 AN: 67844 AF XY: 0.00923

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00583

Gnomad EAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00967

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00422 AC: 1106 AN: 262084 Hom.: 1 Cov.: 5 AF XY: 0.00411 AC XY: 612 AN XY: 148964

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

African (AFR) AF: 0.00636 AC: 35 AN: 5506

American (AMR) AF: 0.00806 AC: 171 AN: 21206

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 42 AN: 9000

East Asian (EAS) AF: 0.00915 AC: 67 AN: 7322

South Asian (SAS) AF: 0.00259 AC: 131 AN: 50568

European-Finnish (FIN) AF: 0.00572 AC: 95 AN: 16598

Middle Eastern (MID) AF: 0.00302 AC: 3 AN: 994

European-Non Finnish (NFE) AF: 0.00370 AC: 513 AN: 138754

Other (OTH) AF: 0.00404 AC: 49 AN: 12136

⚠️ 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: 0.000552 AC: 71 AN: 128574 Hom.: 0 Cov.: 27 AF XY: 0.000534 AC XY: 33 AN XY: 61794

African (AFR) AF: 0.00114 AC: 40 AN: 34966

American (AMR) AF: 0.000377 AC: 5 AN: 13268

Ashkenazi Jewish (ASJ) AF: 0.000322 AC: 1 AN: 3108

East Asian (EAS) AF: 0.000492 AC: 2 AN: 4066

South Asian (SAS) AF: 0.000288 AC: 1 AN: 3474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.000353 AC: 21 AN: 59560

Other (OTH) AF: 0.000571 AC: 1 AN: 1752

Alfa AF: 0.0144 Hom.: 34

Bravo AF: 0.000518

ClinVar

ClinVar submissions

Significance: Likely 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		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;