Genetic Variant VCP:p.Arg155His (chr9-35065363-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_007126.5(VCP):c.464G>A(p.Arg155His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VCP
NM_007126.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.77

Publications

204 publications found

Variant links:

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

VCP links:

ENSG00000288699 (HGNC:):

ENSG00000288699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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, 11 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 chr9-35065363-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8472.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

PP5

Variant 9-35065363-C-T is Pathogenic according to our data. Variant chr9-35065363-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCP	NM_007126.5	MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 17	NP_009057.1	P55072
VCP	NM_001354927.2		c.329G>A	p.Arg110His	missense	Exon 5 of 17	NP_001341856.1	C9JUP7
VCP	NM_001354928.2		c.329G>A	p.Arg110His	missense	Exon 5 of 17	NP_001341857.1	C9JUP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VCP	ENST00000358901.11	TSL:1 MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 17	ENSP00000351777.6	P55072
ENSG00000288699	ENST00000681845.1		n.*562G>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000505452.1	A0A7P0T910
ENSG00000288699	ENST00000681845.1		n.*562G>A		3_prime_UTR	Exon 5 of 5	ENSP00000505452.1	A0A7P0T910

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (4)

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)

Inborn genetic diseases (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

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.8

PhyloP100

7.8

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.73

Sift

Benign

0.12

Sift4G

Benign

0.17

Polyphen

0.95

Vest4

0.89

MutPred

0.64

Loss of MoRF binding (P = 0.0084)

MVP

0.97

MPC

1.7

ClinPred

0.99

GERP RS

6.1

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.80

gMVP

0.85

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over