rs1554668804

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The ENST00000358901.11(VCP):​c.479C>T​(p.Ala160Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A160P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

VCP
ENST00000358901.11 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.82
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000358901.11
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-35065349-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532761.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, not_provided=1}.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCP. . Gene score misZ 5.4064 (greater than the threshold 3.09). Trascript score misZ 8.1614 (greater than threshold 3.09). GenCC has associacion of gene with spastic paraplegia-Paget disease of bone syndrome, adult-onset distal myopathy due to VCP mutation, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, Charcot-Marie-Tooth disease type 2Y, amyotrophic lateral sclerosis, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, frontotemporal dementia with motor neuron disease, inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VCPNM_007126.5 linkuse as main transcriptc.479C>T p.Ala160Val missense_variant 5/17 ENST00000358901.11 NP_009057.1
VCPNM_001354927.2 linkuse as main transcriptc.344C>T p.Ala115Val missense_variant 5/17 NP_001341856.1
VCPNM_001354928.2 linkuse as main transcriptc.344C>T p.Ala115Val missense_variant 5/17 NP_001341857.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VCPENST00000358901.11 linkuse as main transcriptc.479C>T p.Ala160Val missense_variant 5/171 NM_007126.5 ENSP00000351777 P3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 26, 2022This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 160 of the VCP protein (p.Ala160Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt VCP protein function. ClinVar contains an entry for this variant (Variation ID: 532758). This variant has not been reported in the literature in individuals affected with VCP-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;D;T
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Uncertain
0.61
D;D;D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Uncertain
2.1
M;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-2.0
N;N;N
REVEL
Uncertain
0.41
Sift
Benign
0.15
T;T;D
Sift4G
Benign
0.17
T;.;.
Polyphen
0.017
B;.;.
Vest4
0.69
MutPred
0.35
Loss of sheet (P = 0.0817);.;.;
MVP
0.93
MPC
1.4
ClinPred
0.93
D
GERP RS
6.1
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.75
gMVP
0.87

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

LitVar

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

Other links and lift over

dbSNP: rs1554668804; hg19: chr9-35065345; API