rs10972300

Variant names:

• chr9-35068204-C-T
• rs10972300
• NM_007126.5:c.129+47G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007126.5(VCP):​c.129+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,607,896 control chromosomes in the GnomAD database, including 36,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2760 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33607 hom.)
• Consequence: VCP NM_007126.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.326
• Publications: 18 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

ENSG00000288699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-35068204-C-T is Benign according to our data. Variant chr9-35068204-C-T is described in ClinVar as Benign. ClinVar VariationId is 260121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.129+47G>A		intron_variant	Intron 2 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.-7+47G>A		intron_variant	Intron 2 of 16		NP_001341856.1
VCP	NM_001354928.2	c.-7+47G>A		intron_variant	Intron 2 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.129+47G>A		intron_variant	Intron 2 of 16	1	NM_007126.5	ENSP00000351777.6
ENSG00000288699	ENST00000681845.1	n.*227+47G>A		intron_variant	Intron 2 of 4			ENSP00000505452.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27373 AN: 152014 Hom.: 2756 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.185 AC: 46549 AN: 251214 AF XY: 0.190

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.0816

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.210 AC: 306066 AN: 1455764 Hom.: 33607 Cov.: 30 AF XY: 0.210 AC XY: 152479 AN XY: 724646

African (AFR) AF: 0.134 AC: 4463 AN: 33380

American (AMR) AF: 0.168 AC: 7515 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7318 AN: 26096

East Asian (EAS) AF: 0.0645 AC: 2559 AN: 39670

South Asian (SAS) AF: 0.237 AC: 20375 AN: 86104

European-Finnish (FIN) AF: 0.109 AC: 5806 AN: 53224

Middle Eastern (MID) AF: 0.218 AC: 1236 AN: 5670

European-Non Finnish (NFE) AF: 0.221 AC: 244128 AN: 1106732

Other (OTH) AF: 0.211 AC: 12666 AN: 60170

GnomAD4 genome AF: 0.180 AC: 27401 AN: 152132 Hom.: 2760 Cov.: 32 AF XY: 0.177 AC XY: 13175 AN XY: 74368

African (AFR) AF: 0.138 AC: 5747 AN: 41500

American (AMR) AF: 0.195 AC: 2980 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 986 AN: 3464

East Asian (EAS) AF: 0.0785 AC: 407 AN: 5184

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4818

European-Finnish (FIN) AF: 0.102 AC: 1086 AN: 10598

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14322 AN: 67976

Other (OTH) AF: 0.184 AC: 389 AN: 2114

Alfa AF: 0.200 Hom.: 8393

Bravo AF: 0.183

Asia WGS AF: 0.148 AC: 518 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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

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:1

Dec 05, 2021

Genome-Nilou Lab

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	-0.57
CADD	Benign	18
DANN	Benign	0.76
PhyloP100		0.33
PromoterAI		0.0066	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10972300; hg19: chr9-35068201; COSMIC: COSV107444757;