rs1554668805

Positions:

• chr9-35065349-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_007126.5(VCP):​c.478G>C​(p.Ala160Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.77

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]

ENSG00000288699 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 9-35065349-C-G is Pathogenic according to our data. 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: {Uncertain_significance=1, not_provided=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCP	NM_007126.5	c.478G>C	p.Ala160Pro	missense_variant	5/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.343G>C	p.Ala115Pro	missense_variant	5/17		NP_001341856.1
VCP	NM_001354928.2	c.343G>C	p.Ala115Pro	missense_variant	5/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.478G>C	p.Ala160Pro	missense_variant	5/17	1	NM_007126.5	ENSP00000351777.6
ENSG00000288699	ENST00000681845.1	n.*576G>C		non_coding_transcript_exon_variant	5/5			ENSP00000505452.1
ENSG00000288699	ENST00000681845.1	n.*576G>C		3_prime_UTR_variant	5/5			ENSP00000505452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 160 of the VCP protein (p.Ala160Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of VCP-related conditions and/or inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (PMID: 28692196, 29754758; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 532761). 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 with a negative predictive value of 80%. This variant disrupts the p.Ala160 amino acid residue in VCP. Other variant(s) that disrupt this residue have been observed in individuals with VCP-related conditions (PMID: 36980948), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 11-27-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T;T
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.95	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.26	T;T;D
Sift4G	Benign	0.40	T;.;.
Polyphen		0.0020	B;.;.
Vest4		0.86
MutPred		0.43		Loss of sheet (P = 0.0315);.;.;
MVP		0.98
MPC		1.7
ClinPred		0.90	D
GERP RS		6.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.86
gMVP		0.98

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

Other links and lift over

dbSNP: rs1554668805; hg19: chr9-35065346;