VAPB p.Asp130Glu

Variant names:

• chr20-58439019-T-A
• NM_004738.5:c.390T>A
• VAPB p.Asp130Glu

Your query was ambiguous. Multiple possible variants found:

• chr20-58439019-T-A
• chr20-58439019-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004738.5(VAPB):​c.390T>A​(p.Asp130Glu) variant causes a missense 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• 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, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22646904).

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.390T>A	p.Asp130Glu	missense	Exon 4 of 6	NP_004729.1	O95292-1
	VAPB	NM_001195677.2		c.212-5058T>A		intron	N/A	NP_001182606.1	O95292-2
	VAPB	NR_036633.2		n.443-1888T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAPB	ENST00000475243.6	TSL:1 MANE Select	c.390T>A	p.Asp130Glu	missense	Exon 4 of 6	ENSP00000417175.1	O95292-1
	VAPB	ENST00000395802.7	TSL:1	c.212-5058T>A		intron	N/A	ENSP00000379147.3	O95292-2
	VAPB	ENST00000903510.1		c.450T>A	p.Asp150Glu	missense	Exon 5 of 7	ENSP00000573569.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Benign	0.27	T
Sift4G	Benign	0.60	T
Varity_R		0.11
gMVP		0.056
Mutation Taster		=65/35	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-57014075;