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: 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: 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).

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.194C>T	p.Ala65Val	missense	Exon 2 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.194C>T	p.Ala65Val	missense	Exon 2 of 3	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.425C>T		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.194C>T	p.Ala65Val	missense	Exon 2 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.194C>T	p.Ala65Val	missense	Exon 2 of 3	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.254C>T	p.Ala85Val	missense	Exon 3 of 7	ENSP00000573569.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.38	B
Vest4		0.30
MutPred		0.40		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;