chr9-35062975-C-T

Variant names:

• chr9-35062975-C-T
• rs514492
• NM_007126.5:c.811+3G>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.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
• Publications: 35 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: Orphanet, ClinGen
• Charcot-Marie-Tooth disease type 2Y

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• frontotemporal dementia and/or amyotrophic lateral sclerosis 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -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 VariationId is 260128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.782 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	NM_007126.5	MANE Select	c.811+3G>A		splice_region intron	N/A	NP_009057.1	P55072
	VCP	NM_001354927.2		c.676+3G>A		splice_region intron	N/A	NP_001341856.1	C9JUP7
	VCP	NM_001354928.2		c.676+3G>A		splice_region intron	N/A	NP_001341857.1	C9JUP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.811+3G>A		splice_region intron	N/A	ENSP00000351777.6	P55072
	VCP	ENST00000969527.1		c.811+3G>A		splice_region intron	N/A	ENSP00000639586.1
	VCP	ENST00000940607.1		c.808+3G>A		splice_region intron	N/A	ENSP00000610666.1

Frequencies

GnomAD3 genomes AF: 0.751 AC: 113948 AN: 151688 Hom.: 43123 Cov.: 30

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

GnomAD2 exomes AF: 0.746 AC: 187694 AN: 251442 AF XY: 0.745

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 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.: 43 AF XY: 0.764 AC XY: 555622 AN XY: 727068

African (AFR) AF: 0.745 AC: 24949 AN: 33474

American (AMR) AF: 0.840 AC: 37559 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 20478 AN: 26134

East Asian (EAS) AF: 0.490 AC: 19432 AN: 39686

South Asian (SAS) AF: 0.712 AC: 61446 AN: 86244

European-Finnish (FIN) AF: 0.719 AC: 38382 AN: 53394

Middle Eastern (MID) AF: 0.743 AC: 4284 AN: 5766

European-Non Finnish (NFE) AF: 0.779 AC: 866425 AN: 1111646

Other (OTH) AF: 0.751 AC: 45336 AN: 60378

GnomAD4 genome AF: 0.751 AC: 114029 AN: 151804 Hom.: 43154 Cov.: 30 AF XY: 0.747 AC XY: 55419 AN XY: 74184

African (AFR) AF: 0.738 AC: 30532 AN: 41370

American (AMR) AF: 0.794 AC: 12093 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2744 AN: 3470

East Asian (EAS) AF: 0.458 AC: 2348 AN: 5124

South Asian (SAS) AF: 0.707 AC: 3404 AN: 4814

European-Finnish (FIN) AF: 0.719 AC: 7558 AN: 10516

Middle Eastern (MID) AF: 0.767 AC: 224 AN: 292

European-Non Finnish (NFE) AF: 0.778 AC: 52907 AN: 67966

Other (OTH) AF: 0.746 AC: 1575 AN: 2110

Alfa AF: 0.775 Hom.: 144372

Bravo AF: 0.758

Asia WGS AF: 0.583 AC: 2028 AN: 3478

EpiCase AF: 0.779

EpiControl AF: 0.772

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (2)
-	-	2	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (2)
-	-	1	Charcot-Marie-Tooth disease type 2Y (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.66
PhyloP100		0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=42/58	polymorphism (auto)

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

Other links and lift over

dbSNP: rs514492; hg19: chr9-35062972; COSMIC: COSV62719673; COSMIC: COSV62719673;