NM_007126.5:c.1092C>T

Variant names:

• chr9-35061679-G-A
• rs61752947
• NM_007126.5:c.1092C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007126.5(VCP):​c.1092C>T​(p.Asp364Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.001 in 1,556,602 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 0.0056 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (12 hom.)
• Consequence: VCP NM_007126.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.26
• 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: 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=-0.51).
• BP6: Variant 9-35061679-G-A is Benign according to our data. Variant chr9-35061679-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 366718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0056 (769/137296) while in subpopulation AFR AF = 0.0189 (743/39330). AF 95% confidence interval is 0.0178. There are 13 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 769 AD gene.

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.1092C>T	p.Asp364Asp	synonymous	Exon 10 of 17	NP_009057.1	P55072
	VCP	NM_001354927.2		c.957C>T	p.Asp319Asp	synonymous	Exon 10 of 17	NP_001341856.1	C9JUP7
	VCP	NM_001354928.2		c.957C>T	p.Asp319Asp	synonymous	Exon 10 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.1092C>T	p.Asp364Asp	synonymous	Exon 10 of 17	ENSP00000351777.6	P55072
	VCP	ENST00000969527.1		c.1092C>T	p.Asp364Asp	synonymous	Exon 10 of 18	ENSP00000639586.1
	VCP	ENST00000940607.1		c.1089C>T	p.Asp363Asp	synonymous	Exon 10 of 17	ENSP00000610666.1

Frequencies

GnomAD3 genomes AF: 0.00559 AC: 767 AN: 137174 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000333

Gnomad OTH AF: 0.00319

GnomAD2 exomes AF: 0.00151 AC: 334 AN: 220474 AF XY: 0.00114

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.000722

GnomAD4 exome AF: 0.000555 AC: 788 AN: 1419306 Hom.: 12 Cov.: 33 AF XY: 0.000497 AC XY: 352 AN XY: 707800

African (AFR) AF: 0.0192 AC: 640 AN: 33250

American (AMR) AF: 0.000814 AC: 36 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5688

European-Non Finnish (NFE) AF: 0.0000233 AC: 25 AN: 1073380

Other (OTH) AF: 0.00129 AC: 76 AN: 58904

GnomAD4 genome AF: 0.00560 AC: 769 AN: 137296 Hom.: 13 Cov.: 32 AF XY: 0.00557 AC XY: 373 AN XY: 66966

African (AFR) AF: 0.0189 AC: 743 AN: 39330

American (AMR) AF: 0.00136 AC: 18 AN: 13230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3130

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000333 AC: 2 AN: 59992

Other (OTH) AF: 0.00315 AC: 6 AN: 1902

Alfa AF: 0.00206 Hom.: 2

Bravo AF: 0.00564

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)
-	-	1	VCP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.9
DANN	Benign	0.51
PhyloP100		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61752947; hg19: chr9-35061676;