ENST00000479300.2:n.1102G>T

Variant names:

• chr9-35056964-C-A
• rs1053318
• ENST00000479300.2:n.1102G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000479300.2(VCP):​n.1102G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 761,896 control chromosomes in the GnomAD database, including 16,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3031 hom., cov: 33)
  • Exomes 𝑓: 0.20 (13052 hom.)
• Consequence: VCP ENST00000479300.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.395
• Publications: 19 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-35056964-C-A is Benign according to our data. Variant chr9-35056964-C-A is described in ClinVar as [Benign]. Clinvar id is 366714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.*153G>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.*153G>T		3_prime_UTR_variant	Exon 17 of 17		NP_001341856.1
VCP	NM_001354928.2	c.*153G>T		3_prime_UTR_variant	Exon 17 of 17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.*153G>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29167 AN: 152102 Hom.: 3028 Cov.: 33

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.195

GnomAD4 exome AF: 0.201 AC: 122490 AN: 609676 Hom.: 13052 Cov.: 8 AF XY: 0.203 AC XY: 66166 AN XY: 325748

African (AFR) AF: 0.178 AC: 2937 AN: 16460

American (AMR) AF: 0.179 AC: 5512 AN: 30766

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 5369 AN: 19096

East Asian (EAS) AF: 0.0617 AC: 2041 AN: 33084

South Asian (SAS) AF: 0.236 AC: 15200 AN: 64366

European-Finnish (FIN) AF: 0.110 AC: 4069 AN: 36914

Middle Eastern (MID) AF: 0.216 AC: 577 AN: 2674

European-Non Finnish (NFE) AF: 0.214 AC: 80171 AN: 374228

Other (OTH) AF: 0.206 AC: 6614 AN: 32088

GnomAD4 genome AF: 0.192 AC: 29187 AN: 152220 Hom.: 3031 Cov.: 33 AF XY: 0.188 AC XY: 13995 AN XY: 74414

African (AFR) AF: 0.178 AC: 7408 AN: 41516

American (AMR) AF: 0.200 AC: 3052 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 988 AN: 3472

East Asian (EAS) AF: 0.0778 AC: 403 AN: 5182

South Asian (SAS) AF: 0.240 AC: 1161 AN: 4828

European-Finnish (FIN) AF: 0.103 AC: 1089 AN: 10604

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14355 AN: 68008

Other (OTH) AF: 0.196 AC: 413 AN: 2112

Alfa AF: 0.204 Hom.: 5977

Bravo AF: 0.196

Asia WGS AF: 0.147 AC: 513 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1053318; hg19: chr9-35056961;