rs781691837

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004738.5(VAPB):c.111C>A(p.Asp37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. D37H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

VAPB
NM_004738.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Publications

0 publications found

Variant links:

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

VAPB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24516368).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VAPB	NM_004738.5 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 3		NP_001182606.1
VAPB	NR_036633.2 link	n.342C>A		non_coding_transcript_exon_variant	Exon 2 of 4
VAPB	XR_001754433.3 link	n.342C>A		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VAPB	ENST00000475243.6 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 6	1	NM_004738.5	ENSP00000417175.1
VAPB	ENST00000395802.7 link	c.111C>A	p.Asp37Glu	missense_variant	Exon 2 of 3	1		ENSP00000379147.3
VAPB	ENST00000265619.6 link	n.409C>A		non_coding_transcript_exon_variant	Exon 3 of 6	2
VAPB	ENST00000520497.1 link	n.111C>A		non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000430426.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jun 20, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 579701). This variant has not been reported in the literature in individuals affected with VAPB-related conditions. This variant is present in population databases (rs781691837, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 37 of the VAPB protein (p.Asp37Glu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.7

L;L

PhyloP100

1.3

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.15

Sift

Benign

0.042

D;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0010

B;P

Vest4

0.35

MutPred

0.55

Gain of MoRF binding (P = 0.1348);Gain of MoRF binding (P = 0.1348);

MVP

0.45

MPC

0.42

ClinPred

0.74

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.31

Mutation Taster

=57/43

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over