rs1555813002

Variant names:

• chr20-58418346-C-T
• rs1555813002
• NM_004738.5:c.194C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004738.5(VAPB):​c.194C>T​(p.Ala65Val) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65T) has been classified 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: 6.17
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2730673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5	c.194C>T	p.Ala65Val	missense_variant	Exon 2 of 6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.194C>T	p.Ala65Val	missense_variant	Exon 2 of 3		NP_001182606.1
VAPB	NR_036633.2	n.425C>T		non_coding_transcript_exon_variant	Exon 2 of 4
VAPB	XR_001754433.3	n.425C>T		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.194C>T	p.Ala65Val	missense_variant	Exon 2 of 6	1	NM_004738.5	ENSP00000417175.1
VAPB	ENST00000395802.7	c.194C>T	p.Ala65Val	missense_variant	Exon 2 of 3	1		ENSP00000379147.3
VAPB	ENST00000265619.6	n.492C>T		non_coding_transcript_exon_variant	Exon 3 of 6	2
VAPB	ENST00000520497.1	n.194C>T		non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000430426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with VAPB-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 65 of the VAPB protein (p.Ala65Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		6.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.20
Sift	Benign	0.11	T;D
Sift4G	Benign	0.19	T;D
Polyphen		0.38	B;B
Vest4		0.30
MutPred		0.40		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.42
MPC		0.52
ClinPred		0.91	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.22
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555813002; hg19: chr20-56993402;