9-35060305-T-C

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.1695+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,613,318 control chromosomes in the GnomAD database, including 362,752 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 26017 hom., cov: 33)

Exomes 𝑓: 0.67 ( 336735 hom. )

Consequence

VCP
NM_007126.5 splice_region, intron

Scores

Splicing: ADA: 0.00003988

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.129

Publications

27 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: ClinGen, Orphanet
Charcot-Marie-Tooth disease type 2Y
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
frontotemporal dementia and/or amyotrophic lateral sclerosis 6
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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:

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=-0.74).

BP6

Variant 9-35060305-T-C is Benign according to our data. Variant chr9-35060305-T-C is described in ClinVar as Benign. ClinVar VariationId is 260124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
VCP	NM_007126.5 link	c.1695+8A>G	splice_region_variant, intron_variant	Intron 13 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 link	c.1560+8A>G	splice_region_variant, intron_variant	Intron 13 of 16		NP_001341856.1
VCP	NM_001354928.2 link	c.1560+8A>G	splice_region_variant, intron_variant	Intron 13 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11 link	c.1695+8A>G		splice_region_variant, intron_variant	Intron 13 of 16	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes

AF:

0.546

AC:

83057

AN:

152050

Hom.:

26006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.659

Gnomad ASJ

AF:

0.664

Gnomad EAS

AF:

0.0838

Gnomad SAS

AF:

0.481

Gnomad FIN

AF:

0.606

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.709

Gnomad OTH

AF:

0.587

GnomAD2 exomes

AF:

0.592

AC:

148418

AN:

250840

AF XY:

0.596

show subpopulations

Gnomad AFR exome

AF:

0.265

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.668

Gnomad EAS exome

AF:

0.0848

Gnomad FIN exome

AF:

0.610

Gnomad NFE exome

AF:

0.709

Gnomad OTH exome

AF:

0.640

GnomAD4 exome

AF:

0.665

AC:

971828

AN:

1461150

Hom.:

336735

Cov.:

AF XY:

0.662

AC XY:

480937

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.255

AC:

8543

AN:

33462

American (AMR)

AF:

0.666

AC:

29756

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.663

AC:

17328

AN:

26130

East Asian (EAS)

AF:

0.0688

AC:

2730

AN:

39696

South Asian (SAS)

AF:

0.505

AC:

43507

AN:

86234

European-Finnish (FIN)

AF:

0.607

AC:

32420

AN:

53402

Middle Eastern (MID)

AF:

0.598

AC:

3446

AN:

5764

European-Non Finnish (NFE)

AF:

0.717

AC:

796587

AN:

1111408

Other (OTH)

AF:

0.621

AC:

37511

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16868

33736

50605

67473

84341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19472

38944

58416

77888

97360

<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:

0.546

AC:

83100

AN:

152168

Hom.:

26017

Cov.:

AF XY:

0.540

AC XY:

40184

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.273

AC:

11332

AN:

41528

American (AMR)

AF:

0.659

AC:

10077

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.664

AC:

2303

AN:

3470

East Asian (EAS)

AF:

0.0839

AC:

435

AN:

5182

South Asian (SAS)

AF:

0.481

AC:

2319

AN:

4818

European-Finnish (FIN)

AF:

0.606

AC:

6407

AN:

10568

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.709

AC:

48181

AN:

67986

Other (OTH)

AF:

0.585

AC:

1237

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1637

3275

4912

6550

8187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.651

Hom.:

21283

Bravo

AF:

0.536

Asia WGS

AF:

0.303

AC:

1059

AN:

3478

EpiCase

AF:

0.703

EpiControl

AF:

0.703

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29851785) -

Jul 21, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2Y

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.2

(source)

DANN

Benign

0.82

PhyloP100

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over