Genetic Variant NM_004738.5: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: 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VAPB	NM_004738.5 link	c.58+711T>C	intron_variant	Intron 1 of 5	ENST00000475243.6	NP_004729.1	O95292-1Q53XM7
VAPB	NM_001195677.2 link	c.58+711T>C	intron_variant	Intron 1 of 2		NP_001182606.1	O95292-2
VAPB	NR_036633.2 link	n.289+711T>C	intron_variant	Intron 1 of 3
VAPB	XR_001754433.3 link	n.289+711T>C	intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
VAPB	ENST00000475243.6 link	c.58+711T>C	intron_variant	Intron 1 of 5	1	NM_004738.5	ENSP00000417175.1	O95292-1
VAPB	ENST00000395802.7 link	c.58+711T>C	intron_variant	Intron 1 of 2	1		ENSP00000379147.3	O95292-2
VAPB	ENST00000265619.6 link	n.244T>C	non_coding_transcript_exon_variant	Exon 2 of 6	2
VAPB	ENST00000520497.1 link	n.58+711T>C	intron_variant	Intron 1 of 3	2		ENSP00000430426.1	E5RK64

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 v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over