rs374391034

Variant names:

• chr9-35057477-T-C
• rs374391034
• NM_007126.5:c.2214A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007126.5(VCP):​c.2214A>G​(p.Glu738Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,614,042 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: VCP NM_007126.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.27
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-35057477-T-C is Benign according to our data. Variant chr9-35057477-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000807 (123/152384) while in subpopulation SAS AF = 0.0249 (120/4824). AF 95% confidence interval is 0.0213. There are 2 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.2214A>G	p.Glu738Glu	synonymous_variant	Exon 16 of 17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.2079A>G	p.Glu693Glu	synonymous_variant	Exon 16 of 17		NP_001341856.1
VCP	NM_001354928.2	c.2079A>G	p.Glu693Glu	synonymous_variant	Exon 16 of 17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.2214A>G	p.Glu738Glu	synonymous_variant	Exon 16 of 17	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes AF: 0.000814 AC: 124 AN: 152266 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00223 AC: 561 AN: 251074 AF XY: 0.00310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00111 AC: 1619 AN: 1461658 Hom.: 23 Cov.: 32 AF XY: 0.00159 AC XY: 1158 AN XY: 727154

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0177 AC: 1530 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53192

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112006

Other (OTH) AF: 0.00126 AC: 76 AN: 60394

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152384 Hom.: 2 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74518

African (AFR) AF: 0.0000481 AC: 2 AN: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0249 AC: 120 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000545 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 29, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 06, 2015

Eurofins Ntd Llc (ga)

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:1

Jan 12, 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. -

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

Jan 12, 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

Dec 26, 2024

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	10
DANN	Benign	0.78
PhyloP100		1.3
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism

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: rs374391034; hg19: chr9-35057474; COSMIC: COSV62721347; COSMIC: COSV62721347;