Variant 20-58389490-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_004738.5(VAPB):c.31G>C(p.Glu11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VAPB
NM_004738.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain MSP (size 117) in uniprot entity VAPB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004738.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29910037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VAPB	NM_004738.5 linkuse as main transcript	c.31G>C	p.Glu11Gln	missense_variant	1/6	ENST00000475243.6
VAPB	NM_001195677.2 linkuse as main transcript	c.31G>C	p.Glu11Gln	missense_variant	1/3
VAPB	NR_036633.2 linkuse as main transcript	n.262G>C		non_coding_transcript_exon_variant	1/4
VAPB	XR_001754433.3 linkuse as main transcript	n.262G>C		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAPB	ENST00000475243.6 linkuse as main transcript	c.31G>C	p.Glu11Gln	missense_variant	1/6	1	NM_004738.5	P1	O95292-1
VAPB	ENST00000395802.7 linkuse as main transcript	c.31G>C	p.Glu11Gln	missense_variant	1/3	1			O95292-2
VAPB	ENST00000265619.6 linkuse as main transcript	n.116G>C		non_coding_transcript_exon_variant	1/6	2
VAPB	ENST00000520497.1 linkuse as main transcript	c.31G>C	p.Glu11Gln	missense_variant, NMD_transcript_variant	1/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443270

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716588

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 15, 2022

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"). 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). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 11 of the VAPB protein (p.Glu11Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

D;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.21

Sift

Benign

0.066

T;T

Sift4G

Benign

0.068

T;T

Polyphen

0.24

B;B

Vest4

0.37

MutPred

0.44

Loss of catalytic residue at E11 (P = 0.0806);Loss of catalytic residue at E11 (P = 0.0806);

MVP

0.53

MPC

0.53

ClinPred

0.80

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over