chr20-58389453-A-G

Variant names:

• chr20-58389453-A-G
• NM_004738.5:c.-7A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004738.5(VAPB):​c.-7A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VAPB NM_004738.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0630
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 20-58389453-A-G is Benign according to our data. Variant chr20-58389453-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3354206.Status of the report is no_assertion_criteria_provided, 0 stars.

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.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_004729.1	O95292-1
	VAPB	NM_004738.5	MANE Select	c.-7A>G		5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001182606.1	O95292-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.-7A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000379147.3	O95292-2
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.-7A>G		5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715338

African (AFR) AF: 0.00 AC: 0 AN: 32688

American (AMR) AF: 0.00 AC: 0 AN: 42554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 38626

South Asian (SAS) AF: 0.00 AC: 0 AN: 82608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102518

Other (OTH) AF: 0.00 AC: 0 AN: 59510

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	VAPB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		0.063
PromoterAI		0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=293/7	polymorphism

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

hg19: chr20-56964509;