rs146459055

Positions:

• chr20-58439019-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004738.5(VAPB):​c.390T>G​(p.Asp130Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,612,812 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (3 hom.)
• Consequence: VAPB NM_004738.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.70

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00932765).
• BP6: Variant 20-58439019-T-G is Benign according to our data. Variant chr20-58439019-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 259538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58439019-T-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAPB	NM_004738.5	c.390T>G	p.Asp130Glu	missense_variant	4/6	ENST00000475243.6	NP_004729.1
VAPB	NM_001195677.2	c.212-5058T>G		intron_variant			NP_001182606.1
VAPB	XR_001754433.3	n.621T>G		non_coding_transcript_exon_variant	4/6
VAPB	NR_036633.2	n.443-1888T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6	c.390T>G	p.Asp130Glu	missense_variant	4/6	1	NM_004738.5	ENSP00000417175.1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00130 AC: 326 AN: 250816 Hom.: 1 AF XY: 0.00118 AC XY: 160 AN XY: 135672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000729 AC: 1064 AN: 1460460 Hom.: 3 Cov.: 30 AF XY: 0.000764 AC XY: 555 AN XY: 726644

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00540

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000731

Gnomad4 FIN exome AF: 0.000301

Gnomad4 NFE exome AF: 0.000579

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74514

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000827

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.00142

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	This variant is associated with the following publications: (PMID: 18322265, 22878164, 23971766, 19183264, 28430856, 25382069) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Amyotrophic lateral sclerosis type 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Adult-onset proximal spinal muscular atrophy, autosomal dominant Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2019

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 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

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.097
Sift	Benign	0.27	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.68
MutPred		0.28		Gain of methylation at K131 (P = 0.0902);
MVP		0.15
MPC		0.42
ClinPred		0.018	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.056

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

LitVar

Other links and lift over

dbSNP: rs146459055; hg19: chr20-57014075;