9-35062975-C-T

Position:

chr9-35062975-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

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 links:

VCP (HGNC:):

VCP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	MANE	Protein
VCP	NM_007126.5 linkuse as main transcript	c.811+3G>A	splice_region_variant, intron_variant	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 linkuse as main transcript	c.676+3G>A	splice_region_variant, intron_variant		NP_001341856.1
VCP	NM_001354928.2 linkuse as main transcript	c.676+3G>A	splice_region_variant, intron_variant		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11 linkuse as main transcript	c.811+3G>A		splice_region_variant, intron_variant		1	NM_007126.5	ENSP00000351777.6		P55072

Frequencies

GnomAD3 genomes

AF:

0.751

AC:

113948

AN:

151688

Hom.:

43123

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.764

AC XY:

555622

AN XY:

727068

show subpopulations

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.:

AF XY:

0.747

AC XY:

55419

AN XY:

74184

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	This variant is associated with the following publications: (PMID: 29851785, 30954774) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Charcot-Marie-Tooth disease type 2Y

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over