rs1053318

Variant names:

• chr9-35056964-C-A
• rs1053318
• NM_007126.5:c.*153G>T

Variant summary

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

The NM_007126.5(VCP):​c.*153G>T variant causes a 3 prime UTR 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 NM_007126.5 3_prime_UTR
• 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: 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 -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 VariationId 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.

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.*153G>T		3_prime_UTR	Exon 17 of 17	NP_009057.1	P55072
	VCP	NM_001354927.2		c.*153G>T		3_prime_UTR	Exon 17 of 17	NP_001341856.1	C9JUP7
	VCP	NM_001354928.2		c.*153G>T		3_prime_UTR	Exon 17 of 17	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.*153G>T		3_prime_UTR	Exon 17 of 17	ENSP00000351777.6	P55072
	VCP	ENST00000479300.2	TSL:1	n.1102G>T		non_coding_transcript_exon	Exon 4 of 4
	VCP	ENST00000969527.1		c.*153G>T		3_prime_UTR	Exon 18 of 18	ENSP00000639586.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (1)

Computational scores

Source: dbNSFP v4.9

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;