20-58389502-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004738.5(VAPB):c.43G>A(p.Glu15Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain MSP (size 117) in uniprot entity VAPB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004738.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAPB	NM_004738.5	c.43G>A	p.Glu15Lys	missense_variant	1/6	ENST00000475243.6
VAPB	NM_001195677.2	c.43G>A	p.Glu15Lys	missense_variant	1/3
VAPB	NR_036633.2	n.274G>A		non_coding_transcript_exon_variant	1/4
VAPB	XR_001754433.3	n.274G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAPB	ENST00000475243.6	c.43G>A	p.Glu15Lys	missense_variant	1/6	1	NM_004738.5	P1
VAPB	ENST00000395802.7	c.43G>A	p.Glu15Lys	missense_variant	1/3	1
VAPB	ENST00000265619.6	n.128G>A		non_coding_transcript_exon_variant	1/6	2
VAPB	ENST00000520497.1	c.43G>A	p.Glu15Lys	missense_variant, NMD_transcript_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440256 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 714884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The c.43G>A (p.E15K) alteration is located in exon 1 (coding exon 1) of the VAPB gene. This alteration results from a G to A substitution at nucleotide position 43, causing the glutamic acid (E) at amino acid position 15 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.20
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.026	D;T
Polyphen		0.054	B;B
Vest4		0.62
MutPred		0.52		Gain of ubiquitination at E15 (P = 0.0238);Gain of ubiquitination at E15 (P = 0.0238);
MVP		0.33
MPC		0.52
ClinPred		0.72	D
GERP RS		3.4
Varity_R		0.71
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs886340297; hg19: chr20-56964558;