rs779959657

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_007126.5(VCP):c.278G>A(p.Arg93His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,076 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

VCP
NM_007126.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_007126.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-35067916-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 593071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, VCP

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

PP5

Variant 9-35067915-C-T is Pathogenic according to our data. Variant chr9-35067915-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35067915-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VCP	NM_007126.5 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	3/17	ENST00000358901.11
VCP	NM_001354927.2 linkuse as main transcript	c.143G>A	p.Arg48His	missense_variant	3/17
VCP	NM_001354928.2 linkuse as main transcript	c.143G>A	p.Arg48His	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCP	ENST00000358901.11 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	3/17	1	NM_007126.5	P3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135914

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2022

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24123792, 27165006, 35216053) -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This variant is present in population databases (rs779959657, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 93 of the VCP protein (p.Arg93His). This missense change has been observed in individual(s) with inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) (PMID: 24123792, 27165006). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg93 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16790606, 21249466, 22270372, 23333620, 26627873, 27768726). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VCP protein function. ClinVar contains an entry for this variant (Variation ID: 449554). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.090

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.88

Sift

Benign

0.033

D;T;T

Sift4G

Benign

0.16

T;.;.

Polyphen

1.0

D;.;.

Vest4

0.84

MutPred

0.65

Gain of helix (P = 0.005);.;.;

MVP

0.80

MPC

1.7

ClinPred

0.89

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over