20-58389475-C-G

Variant names:

• chr20-58389475-C-G
• NM_004738.5:c.16C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004738.5(VAPB):​c.16C>G​(p.Gln6Glu) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23649931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.16C>G	p.Gln6Glu	missense_variant	Exon 1 of 6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.16C>G	p.Gln6Glu	missense_variant	Exon 1 of 3		NP_001182606.1
VAPB	NR_036633.2	n.247C>G		non_coding_transcript_exon_variant	Exon 1 of 4
VAPB	XR_001754433.3	n.247C>G		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.16C>G	p.Gln6Glu	missense_variant	Exon 1 of 6	1	NM_004738.5	ENSP00000417175.1
VAPB	ENST00000395802.7	c.16C>G	p.Gln6Glu	missense_variant	Exon 1 of 3	1		ENSP00000379147.3
VAPB	ENST00000265619.6	n.101C>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
VAPB	ENST00000520497.1	n.16C>G		non_coding_transcript_exon_variant	Exon 1 of 4	2		ENSP00000430426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant Uncertain:1

Apr 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 6 of the VAPB protein (p.Gln6Glu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This variant has not been reported in the literature in individuals affected with VAPB-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.61	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;T
Sift4G	Uncertain	0.016	D;T
Polyphen		0.62	P;B
Vest4		0.43
MutPred		0.48		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.26
MPC		0.56
ClinPred		0.90	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-56964531;