9-35062975-C-T

Variant names:

• chr9-35062975-C-T
• rs514492
• NM_007126.5:c.811+3G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007126.5(VCP):​c.811+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,613,250 control chromosomes in the GnomAD database, including 473,708 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 0.75 (43154 hom., cov: 30)
  • Exomes 𝑓: 0.77 (430554 hom.)
• Consequence: VCP NM_007126.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004083
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.543

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-35062975-C-T is Benign according to our data. Variant chr9-35062975-C-T is described in ClinVar as [Benign]. Clinvar id is 260128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35062975-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.811+3G>A		splice_region_variant, intron_variant	Intron 7 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.676+3G>A		splice_region_variant, intron_variant	Intron 7 of 16		NP_001341856.1
VCP	NM_001354928.2	c.676+3G>A		splice_region_variant, intron_variant	Intron 7 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.811+3G>A		splice_region_variant, intron_variant	Intron 7 of 16	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes AF: 0.751 AC: 113948 AN: 151688 Hom.: 43123 Cov.: 30

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.794

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.751

GnomAD3 exomes AF: 0.746 AC: 187694 AN: 251442 Hom.: 71257 AF XY: 0.745 AC XY: 101191 AN XY: 135894

Gnomad AFR exome AF: 0.741

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.452

Gnomad SAS exome AF: 0.708

Gnomad FIN exome AF: 0.720

Gnomad NFE exome AF: 0.777

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.765 AC: 1118291 AN: 1461446 Hom.: 430554 Cov.: 43 AF XY: 0.764 AC XY: 555622 AN XY: 727068

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.840

Gnomad4 ASJ exome AF: 0.784

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.712

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.779

Gnomad4 OTH exome AF: 0.751

GnomAD4 genome AF: 0.751 AC: 114029 AN: 151804 Hom.: 43154 Cov.: 30 AF XY: 0.747 AC XY: 55419 AN XY: 74184

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.794

Gnomad4 ASJ AF: 0.791

Gnomad4 EAS AF: 0.458

Gnomad4 SAS AF: 0.707

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.778

Gnomad4 OTH AF: 0.746

Alfa AF: 0.776 Hom.: 97355

Bravo AF: 0.758

Asia WGS AF: 0.583 AC: 2028 AN: 3478

EpiCase AF: 0.779

EpiControl AF: 0.772

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

-

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

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 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29851785, 30954774) -

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

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Benign:2

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. -

Dec 05, 2021

Genome-Nilou Lab

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	-0.47
CADD	Benign	18
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0080
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

LitVar

Other links and lift over

dbSNP: rs514492; hg19: chr9-35062972; COSMIC: COSV62719673; COSMIC: COSV62719673;