chr20-58445517-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_004738.5(VAPB):c.*1282A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 454,294 control chromosomes in the GnomAD database, including 7,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2090 hom., cov: 32)

Exomes 𝑓: 0.17 ( 5060 hom. )

Consequence

VAPB
NM_004738.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.47

Publications

11 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: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 20-58445517-A-G is Benign according to our data. Variant chr20-58445517-A-G is described in ClinVar as Benign. ClinVar VariationId is 338947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5 link	c.*1282A>G	3_prime_UTR_variant	Exon 6 of 6	ENST00000475243.6	NP_004729.1	O95292-1Q53XM7
VAPB	NR_036633.2 link	n.2060A>G	non_coding_transcript_exon_variant	Exon 4 of 4
VAPB	NM_001195677.2 link	c.*1352A>G	3_prime_UTR_variant	Exon 3 of 3		NP_001182606.1	O95292-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAPB	ENST00000475243.6 link	c.*1282A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_004738.5	ENSP00000417175.1		O95292-1

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

23973

AN:

152026

Hom.:

2086

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.0827

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.134

GnomAD2 exomes

AF:

0.163

AC:

22236

AN:

136630

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.0563

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.261

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.168

AC:

50753

AN:

302152

Hom.:

5060

Cov.:

AF XY:

0.179

AC XY:

30767

AN XY:

172210

show subpopulations

African (AFR)

AF:

0.159

AC:

1363

AN:

8548

American (AMR)

AF:

0.0558

AC:

1521

AN:

27270

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

1860

AN:

10786

East Asian (EAS)

AF:

0.317

AC:

2921

AN:

9210

South Asian (SAS)

AF:

0.250

AC:

14874

AN:

59602

European-Finnish (FIN)

AF:

0.250

AC:

3200

AN:

12790

Middle Eastern (MID)

AF:

0.142

AC:

163

AN:

1150

European-Non Finnish (NFE)

AF:

0.143

AC:

22681

AN:

158752

Other (OTH)

AF:

0.155

AC:

2170

AN:

14044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

3028

6055

9083

12110

15138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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

AF:

0.158

AC:

23983

AN:

152142

Hom.:

2090

Cov.:

AF XY:

0.166

AC XY:

12326

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.154

AC:

6390

AN:

41526

American (AMR)

AF:

0.0825

AC:

1262

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

589

AN:

3468

East Asian (EAS)

AF:

0.310

AC:

1605

AN:

5180

South Asian (SAS)

AF:

0.255

AC:

1228

AN:

4816

European-Finnish (FIN)

AF:

0.273

AC:

2880

AN:

10566

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9526

AN:

67970

Other (OTH)

AF:

0.138

AC:

291

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1020

2040

3059

4079

5099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.137

Hom.:

1044

Bravo

AF:

0.140

Asia WGS

AF:

0.258

AC:

895

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 8

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Adult-onset proximal spinal muscular atrophy, autosomal dominant

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over