rs121909329

Positions:

• chr9-35065363-C-A
• chr9-35065363-C-G
• chr9-35065363-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM2 PM5 PP2 PP3_Moderate

The NM_007126.5(VCP):​c.464G>T​(p.Arg155Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_007126.5 (VCP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCP	NM_007126.5	c.464G>T	p.Arg155Leu	missense_variant	5/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.329G>T	p.Arg110Leu	missense_variant	5/17		NP_001341856.1
VCP	NM_001354928.2	c.329G>T	p.Arg110Leu	missense_variant	5/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.464G>T	p.Arg155Leu	missense_variant	5/17	1	NM_007126.5	ENSP00000351777	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.22	T;.;.
Polyphen		0.95	P;.;.
Vest4		0.94
MutPred		0.58		Loss of MoRF binding (P = 0.0056);.;.;
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.98
gMVP		0.95

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: rs121909329; hg19: chr9-35065360;