Genetic Variant VAPB:c.-151_-149dupCCC (chr20-58389302-A-ACCC) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004738.5(VAPB):c.-151_-149dupCCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 400,026 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

VAPB
NM_004738.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.452

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 41 AD gene.

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.-151_-149dupCCC	5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
VAPB	NM_001195677.2		c.-151_-149dupCCC	5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
VAPB	NR_036633.2		n.81_83dupCCC	non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VAPB	ENST00000475243.6	TSL:1 MANE Select	c.-151_-149dupCCC	5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
VAPB	ENST00000903510.1		c.-151_-149dupCCC	5_prime_UTR	Exon 1 of 7	ENSP00000573569.1
VAPB	ENST00000903509.1		c.-151_-149dupCCC	5_prime_UTR	Exon 1 of 5	ENSP00000573568.1

Frequencies

GnomAD3 genomes

AF:

0.000319

AC:

AN:

128500

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000860

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000151

Gnomad ASJ

AF:

0.000322

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000288

Gnomad FIN

AF:

0.00109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000436

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000221

AC:

AN:

67844

AF XY:

0.000212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000768

Gnomad ASJ exome

AF:

0.000216

Gnomad EAS exome

AF:

0.000201

Gnomad FIN exome

AF:

0.000402

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000383

AC:

104

AN:

271526

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

AN XY:

154528

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

5644

American (AMR)

AF:

0.000223

AC:

AN:

22406

Ashkenazi Jewish (ASJ)

AF:

0.000423

AC:

AN:

9450

East Asian (EAS)

AF:

0.000132

AC:

AN:

7564

South Asian (SAS)

AF:

0.000152

AC:

AN:

52742

European-Finnish (FIN)

AF:

0.000879

AC:

AN:

17062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1030

European-Non Finnish (NFE)

AF:

0.000454

AC:

AN:

143134

Other (OTH)

AF:

0.000480

AC:

AN:

12494

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.341

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000319

AC:

AN:

128500

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

AN XY:

61710

show subpopulations

African (AFR)

AF:

0.0000860

AC:

AN:

34870

American (AMR)

AF:

0.000151

AC:

AN:

13258

Ashkenazi Jewish (ASJ)

AF:

0.000322

AC:

AN:

3108

East Asian (EAS)

AF:

0.00

AC:

AN:

4080

South Asian (SAS)

AF:

0.000288

AC:

AN:

3478

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

7354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.000436

AC:

AN:

59574

Other (OTH)

AF:

0.00

AC:

AN:

1736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000472

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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20-58389302-AC-ACCCC

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