chr9-35067910-G-A

Variant names:

• chr9-35067910-G-A
• rs121909332
• NM_007126.5:c.283C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_007126.5(VCP):​c.283C>T​(p.Arg95Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 6.58
• Publications: 48 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_007126.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-35067909-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 595911.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752
• PP5: Variant 9-35067910-G-A is Pathogenic according to our data. Variant chr9-35067910-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 280124.

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.283C>T	p.Arg95Cys	missense	Exon 3 of 17	NP_009057.1
	VCP	NM_001354927.2		c.148C>T	p.Arg50Cys	missense	Exon 3 of 17	NP_001341856.1
	VCP	NM_001354928.2		c.148C>T	p.Arg50Cys	missense	Exon 3 of 17	NP_001341857.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.283C>T	p.Arg95Cys	missense	Exon 3 of 17	ENSP00000351777.6
	ENSG00000288699	ENST00000681845.1		n.*381C>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000505452.1
	ENSG00000288699	ENST00000681845.1		n.*381C>T		3_prime_UTR	Exon 3 of 5	ENSP00000505452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251464 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Amyotrophic lateral sclerosis (1)
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	-	-	Spastic paraplegia (1)
1	-	-	VCP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.61
Sift	Benign	0.040	D
Sift4G	Benign	0.19	T
Polyphen		0.40	B
Vest4		0.49
MutPred		0.67		Loss of MoRF binding (P = 0.0414)
MVP		0.83
MPC		2.1
ClinPred		0.95	D
GERP RS		5.7
PromoterAI		-0.0098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.82
Mutation Taster		=18/82	disease causing (ClinVar)

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: rs121909332; hg19: chr9-35067907; COSMIC: COSV62722119;