dbSNP rs6026230: VAPB:c.58+711T>C (chr20-58390228-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004738.5(VAPB):c.58+711T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 151,910 control chromosomes in the GnomAD database, including 8,886 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 8881 hom., cov: 31)

Exomes 𝑓: 0.33 ( 5 hom. )

Consequence

VAPB
NM_004738.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.612

Publications

6 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004738.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VAPB	NM_004738.5	MANE Select	c.58+711T>C	intron	N/A	NP_004729.1	O95292-1
VAPB	NM_001195677.2		c.58+711T>C	intron	N/A	NP_001182606.1	O95292-2
VAPB	NR_036633.2		n.289+711T>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VAPB	ENST00000475243.6	TSL:1 MANE Select	c.58+711T>C	intron	N/A	ENSP00000417175.1	O95292-1
VAPB	ENST00000395802.7	TSL:1	c.58+711T>C	intron	N/A	ENSP00000379147.3	O95292-2
VAPB	ENST00000903510.1		c.58+711T>C	intron	N/A	ENSP00000573569.1

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49815

AN:

151732

Hom.:

8859

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.284

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.279

Gnomad OTH

AF:

0.308

GnomAD4 exome

AF:

0.333

AC:

AN:

Hom.:

Cov.:

AF XY:

0.361

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.167

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.310

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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

AF:

0.329

AC:

49886

AN:

151850

Hom.:

8881

Cov.:

AF XY:

0.325

AC XY:

24142

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.472

AC:

19528

AN:

41388

American (AMR)

AF:

0.306

AC:

4671

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

880

AN:

3464

East Asian (EAS)

AF:

0.274

AC:

1409

AN:

5150

South Asian (SAS)

AF:

0.117

AC:

566

AN:

4820

European-Finnish (FIN)

AF:

0.271

AC:

2854

AN:

10512

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.279

AC:

18985

AN:

67964

Other (OTH)

AF:

0.307

AC:

646

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1576

3153

4729

6306

7882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

478

956

1434

1912

2390

<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:

0.296

Hom.:

6998

Bravo

AF:

0.339

Asia WGS

AF:

0.219

AC:

763

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.9

(source)

DANN

Benign

0.48

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over