rs566283411

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PM4_SupportingBP6BS2

The NM_004738.5(VAPB):c.479_481del(p.Ser160del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0027 in 1,614,114 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 11 hom. )

Consequence

VAPB
NM_004738.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 5.81

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity VAPB_HUMAN

PM4

Nonframeshift variant in NON repetitive region in NM_004738.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 20-58440983-GTTC-G is Benign according to our data. Variant chr20-58440983-GTTC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}. Variant chr20-58440983-GTTC-G is described in Lovd as [Likely_benign]. Variant chr20-58440983-GTTC-G is described in Lovd as [Benign]. Variant chr20-58440983-GTTC-G is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VAPB	NM_004738.5 linkuse as main transcript	c.479_481del	p.Ser160del	inframe_deletion	5/6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2 linkuse as main transcript	c.212-3088_212-3086del		intron_variant			NP_001182606.1
VAPB	NR_036633.2 linkuse as main transcript	n.525_527del		non_coding_transcript_exon_variant	3/4
VAPB	XR_001754433.3 linkuse as main transcript	n.873_875del		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6 linkuse as main transcript	c.479_481del	p.Ser160del	inframe_deletion	5/6	1	NM_004738.5	ENSP00000417175	P1	O95292-1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00282

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00168

AC:

421

AN:

251172

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00298

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00282

AC:

4117

AN:

1461844

Hom.:

AF XY:

0.00274

AC XY:

1994

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00176

Gnomad4 NFE exome

AF:

0.00345

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152270

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00282

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000362

Hom.:

Bravo

AF:

0.00161

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	This variant is associated with the following publications: (PMID: 21989245, 22878164, 19183264, 18322265, 23971766, 23446633) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	VAPB: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2020	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 12, 2020	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Amyotrophic Lateral Sclerosis, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

VAPB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spinal Muscular Atrophy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over