Genetic Variant NM_004738.5:c.-192_-187dupGCCCTC (chr20-58389257-G-GCCTCGC) – 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.-192_-187dupGCCCTC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 670,770 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 2 hom. )

Consequence

VAPB
NM_004738.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.441

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 47 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.-192_-187dupGCCCTC	5_prime_UTR	Exon 1 of 6	NP_004729.1	O95292-1
VAPB	NM_001195677.2		c.-192_-187dupGCCCTC	5_prime_UTR	Exon 1 of 3	NP_001182606.1	O95292-2
VAPB	NR_036633.2		n.40_45dupGCCCTC	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.-192_-187dupGCCCTC	5_prime_UTR	Exon 1 of 6	ENSP00000417175.1	O95292-1
VAPB	ENST00000903510.1		c.-192_-187dupGCCCTC	5_prime_UTR	Exon 1 of 7	ENSP00000573569.1
VAPB	ENST00000903509.1		c.-192_-187dupGCCCTC	5_prime_UTR	Exon 1 of 5	ENSP00000573568.1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000362

AC:

AN:

115910

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000890

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000438

Gnomad OTH exome

AF:

0.000851

GnomAD4 exome

AF:

0.000507

AC:

263

AN:

518638

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

181

AN XY:

281988

show subpopulations

African (AFR)

AF:

0.0000798

AC:

AN:

12532

American (AMR)

AF:

0.0000616

AC:

AN:

32480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18724

East Asian (EAS)

AF:

0.00

AC:

AN:

29448

South Asian (SAS)

AF:

0.00103

AC:

AN:

60338

European-Finnish (FIN)

AF:

0.000156

AC:

AN:

32068

Middle Eastern (MID)

AF:

0.000429

AC:

AN:

2330

European-Non Finnish (NFE)

AF:

0.000588

AC:

178

AN:

302486

Other (OTH)

AF:

0.000496

AC:

AN:

28232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000309

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41520

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

67966

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000397

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic Lateral Sclerosis, Dominant (1)

Spinal Muscular Atrophy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.44

Mutation Taster

=281/19

polymorphism

(source)

Splicing

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