9-35059793-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_007126.5(VCP):​c.1704A>G​(p.Gln568Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,614,084 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0037 ( 6 hom. )

Consequence

VCP
NM_007126.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.752

Publications

5 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
Variant 9-35059793-T-C is Benign according to our data. Variant chr9-35059793-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.752 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00296 (451/152194) while in subpopulation AMR AF = 0.00727 (111/15268). AF 95% confidence interval is 0.00617. There are 4 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 451 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VCPNM_007126.5 linkc.1704A>G p.Gln568Gln synonymous_variant Exon 14 of 17 ENST00000358901.11 NP_009057.1
VCPNM_001354927.2 linkc.1569A>G p.Gln523Gln synonymous_variant Exon 14 of 17 NP_001341856.1
VCPNM_001354928.2 linkc.1569A>G p.Gln523Gln synonymous_variant Exon 14 of 17 NP_001341857.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VCPENST00000358901.11 linkc.1704A>G p.Gln568Gln synonymous_variant Exon 14 of 17 1 NM_007126.5 ENSP00000351777.6 P55072

Frequencies

GnomAD3 genomes
AF:
0.00297
AC:
451
AN:
152076
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000869
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00728
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00425
Gnomad OTH
AF:
0.00335
GnomAD2 exomes
AF:
0.00274
AC:
685
AN:
250400
AF XY:
0.00258
show subpopulations
Gnomad AFR exome
AF:
0.000804
Gnomad AMR exome
AF:
0.00439
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000462
Gnomad NFE exome
AF:
0.00424
Gnomad OTH exome
AF:
0.00245
GnomAD4 exome
AF:
0.00366
AC:
5346
AN:
1461890
Hom.:
6
Cov.:
32
AF XY:
0.00355
AC XY:
2585
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.000777
AC:
26
AN:
33480
American (AMR)
AF:
0.00420
AC:
188
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000191
AC:
5
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000614
AC:
53
AN:
86258
European-Finnish (FIN)
AF:
0.000599
AC:
32
AN:
53420
Middle Eastern (MID)
AF:
0.00121
AC:
7
AN:
5768
European-Non Finnish (NFE)
AF:
0.00434
AC:
4822
AN:
1112008
Other (OTH)
AF:
0.00353
AC:
213
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
322
644
967
1289
1611
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
182
364
546
728
910
<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:
0.00296
AC:
451
AN:
152194
Hom.:
4
Cov.:
32
AF XY:
0.00318
AC XY:
237
AN XY:
74418
show subpopulations
African (AFR)
AF:
0.000867
AC:
36
AN:
41526
American (AMR)
AF:
0.00727
AC:
111
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00104
AC:
5
AN:
4808
European-Finnish (FIN)
AF:
0.000189
AC:
2
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00425
AC:
289
AN:
68018
Other (OTH)
AF:
0.00331
AC:
7
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
23
46
69
92
115
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00291
Hom.:
0
Bravo
AF:
0.00337
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00502
EpiControl
AF:
0.00504

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:6
Mar 14, 2018
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

VCP: BP4, BP7 -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 27, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22137929, 25618255, 16790606) -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Benign:2
Apr 19, 2017
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Benign:1
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. -

Inborn genetic diseases Benign:1
Jul 11, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

VCP-related disorder Benign:1
Mar 25, 2020
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Benign:1
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. -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
-0.61
CADD
Benign
11
DANN
Benign
0.82
PhyloP100
0.75
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs142577424; hg19: chr9-35059790; API