9-35061696-GACAGTACACAA-GACAGTACACAAACAGTACACAA

Variant names:

• chr9-35061696-G-GACAGTACACAA
• rs11272867
• NM_007126.5:c.1082-18_1082-8dupTTGTGTACTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007126.5(VCP):​c.1082-18_1082-8dupTTGTGTACTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,589,212 control chromosomes in the GnomAD database, including 354,099 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25664 hom., cov: 0)
  • Exomes 𝑓: 0.66 (328435 hom.)
• Consequence: VCP NM_007126.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.10
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-35061696-G-GACAGTACACAA is Benign according to our data. Variant chr9-35061696-G-GACAGTACACAA is described in ClinVar as Benign. ClinVar VariationId is 260119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.701 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	NM_007126.5	MANE Select	c.1082-18_1082-8dupTTGTGTACTGT		splice_region intron	N/A	NP_009057.1
	VCP	NM_001354927.2		c.947-18_947-8dupTTGTGTACTGT		splice_region intron	N/A	NP_001341856.1
	VCP	NM_001354928.2		c.947-18_947-8dupTTGTGTACTGT		splice_region intron	N/A	NP_001341857.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.1082-8_1082-7insTTGTGTACTGT		splice_region intron	N/A	ENSP00000351777.6
	VCP	ENST00000677257.1		c.1076-8_1076-7insTTGTGTACTGT		splice_region intron	N/A	ENSP00000504354.1
	VCP	ENST00000679902.1		c.1082-8_1082-7insTTGTGTACTGT		splice_region intron	N/A	ENSP00000506338.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82335 AN: 151418 Hom.: 25652 Cov.: 0

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.583

GnomAD4 exome AF: 0.659 AC: 947640 AN: 1437676 Hom.: 328435 Cov.: 36 AF XY: 0.656 AC XY: 470496 AN XY: 716972

African (AFR) AF: 0.251 AC: 8313 AN: 33168

American (AMR) AF: 0.663 AC: 29638 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 16909 AN: 25988

East Asian (EAS) AF: 0.0684 AC: 2715 AN: 39668

South Asian (SAS) AF: 0.502 AC: 43049 AN: 85768

European-Finnish (FIN) AF: 0.607 AC: 32369 AN: 53368

Middle Eastern (MID) AF: 0.590 AC: 3378 AN: 5724

European-Non Finnish (NFE) AF: 0.711 AC: 774566 AN: 1089740

Other (OTH) AF: 0.616 AC: 36703 AN: 59582

GnomAD4 genome AF: 0.544 AC: 82379 AN: 151536 Hom.: 25664 Cov.: 0 AF XY: 0.538 AC XY: 39815 AN XY: 74046

African (AFR) AF: 0.271 AC: 11231 AN: 41380

American (AMR) AF: 0.654 AC: 9932 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2269 AN: 3460

East Asian (EAS) AF: 0.0835 AC: 431 AN: 5164

South Asian (SAS) AF: 0.481 AC: 2308 AN: 4802

European-Finnish (FIN) AF: 0.605 AC: 6356 AN: 10504

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.706 AC: 47839 AN: 67756

Other (OTH) AF: 0.581 AC: 1220 AN: 2100

Alfa AF: 0.612 Hom.: 4986

Asia WGS AF: 0.301 AC: 1053 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Aug 14, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 15, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Amyotrophic Lateral Sclerosis, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VCP-related disorder Benign:1

Mar 27, 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).

not provided Benign:1

Jul 06, 2018

GeneDx

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

Inclusion Body Myopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs11272867; hg19: chr9-35061693; COSMIC: COSV107444655; COSMIC: COSV107444655;