NM_007126.5:c.129+47G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007126.5(VCP):c.129+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,607,896 control chromosomes in the GnomAD database, including 36,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2760 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33607 hom. )

Consequence

VCP
NM_007126.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.326

Publications

18 publications found

Variant links:

Genes affected

VCP (HGNC:12666): (valosin containing protein) This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]

VCP Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Charcot-Marie-Tooth disease type 2Y
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
frontotemporal dementia and/or amyotrophic lateral sclerosis 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adult-onset distal myopathy due to VCP mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
frontotemporal dementia with motor neuron disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spastic paraplegia-Paget disease of bone syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

VCP links:

ENSG00000288699 (HGNC:):

ENSG00000288699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 9-35068204-C-T is Benign according to our data. Variant chr9-35068204-C-T is described in ClinVar as Benign. ClinVar VariationId is 260121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007126.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VCP	NM_007126.5	MANE Select	c.129+47G>A	intron	N/A	NP_009057.1	P55072
VCP	NM_001354927.2		c.-7+47G>A	intron	N/A	NP_001341856.1	C9JUP7
VCP	NM_001354928.2		c.-7+47G>A	intron	N/A	NP_001341857.1	C9JUP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VCP	ENST00000358901.11	TSL:1 MANE Select	c.129+47G>A	intron	N/A	ENSP00000351777.6	P55072
ENSG00000288699	ENST00000681845.1		n.*227+47G>A	intron	N/A	ENSP00000505452.1	A0A7P0T910
VCP	ENST00000969527.1		c.129+47G>A	intron	N/A	ENSP00000639586.1

Frequencies

GnomAD3 genomes

AF:

0.180

AC:

27373

AN:

152014

Hom.:

2756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.285

Gnomad EAS

AF:

0.0785

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.185

AC:

46549

AN:

251214

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.0816

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.208

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.210

AC:

306066

AN:

1455764

Hom.:

33607

Cov.:

AF XY:

0.210

AC XY:

152479

AN XY:

724646

show subpopulations

African (AFR)

AF:

0.134

AC:

4463

AN:

33380

American (AMR)

AF:

0.168

AC:

7515

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

7318

AN:

26096

East Asian (EAS)

AF:

0.0645

AC:

2559

AN:

39670

South Asian (SAS)

AF:

0.237

AC:

20375

AN:

86104

European-Finnish (FIN)

AF:

0.109

AC:

5806

AN:

53224

Middle Eastern (MID)

AF:

0.218

AC:

1236

AN:

5670

European-Non Finnish (NFE)

AF:

0.221

AC:

244128

AN:

1106732

Other (OTH)

AF:

0.211

AC:

12666

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

14266

28533

42799

57066

71332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8478

16956

25434

33912

42390

<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:

0.180

AC:

27401

AN:

152132

Hom.:

2760

Cov.:

AF XY:

0.177

AC XY:

13175

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.138

AC:

5747

AN:

41500

American (AMR)

AF:

0.195

AC:

2980

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

986

AN:

3464

East Asian (EAS)

AF:

0.0785

AC:

407

AN:

5184

South Asian (SAS)

AF:

0.242

AC:

1165

AN:

4818

European-Finnish (FIN)

AF:

0.102

AC:

1086

AN:

10598

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14322

AN:

67976

Other (OTH)

AF:

0.184

AC:

389

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1131

2261

3392

4522

5653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.200

Hom.:

8393

Bravo

AF:

0.183

Asia WGS

AF:

0.148

AC:

518

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Charcot-Marie-Tooth disease type 2Y (1)

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.33

PromoterAI

0.0066

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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