chr9-35059793-T-A

Variant names:

• chr9-35059793-T-A
• rs142577424
• NM_007126.5:c.1704A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007126.5(VCP):​c.1704A>T​(p.Gln568His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q568Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.752
• Publications: 5 publications found

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: ClinGen, Orphanet
• Charcot-Marie-Tooth disease type 2Y

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• frontotemporal dementia and/or amyotrophic lateral sclerosis 6

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.1704A>T	p.Gln568His	missense_variant	Exon 14 of 17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.1569A>T	p.Gln523His	missense_variant	Exon 14 of 17		NP_001341856.1
VCP	NM_001354928.2	c.1569A>T	p.Gln523His	missense_variant	Exon 14 of 17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.1704A>T	p.Gln568His	missense_variant	Exon 14 of 17	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.073
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.75
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.024	D
Polyphen		0.55	P
Vest4		0.45
MutPred		0.46		Gain of helix (P = 0.0854);
MVP		0.87
MPC		2.2
ClinPred		0.88	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.85
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs142577424; hg19: chr9-35059790;