9-35068643-A-T

Variant names:

• chr9-35068643-A-T
• rs2073575
• NM_007126.5:c.18-281T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007126.5(VCP):​c.18-281T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 152,248 control chromosomes in the GnomAD database, including 578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.067 (578 hom., cov: 32)
• Consequence: VCP NM_007126.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.465
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Orphanet
• frontotemporal dementia and/or amyotrophic lateral sclerosis 6

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

ENSG00000288699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-35068643-A-T is Benign according to our data. Variant chr9-35068643-A-T is described in ClinVar as Benign. ClinVar VariationId is 1228992.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007126.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	NM_007126.5	MANE Select	c.18-281T>A		intron	N/A	NP_009057.1
	VCP	NM_001354927.2		c.-118-281T>A		intron	N/A	NP_001341856.1
	VCP	NM_001354928.2		c.-118-281T>A		intron	N/A	NP_001341857.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.18-281T>A		intron	N/A	ENSP00000351777.6
	ENSG00000288699	ENST00000681845.1		n.*116-281T>A		intron	N/A	ENSP00000505452.1
	VCP	ENST00000969527.1		c.18-281T>A		intron	N/A	ENSP00000639586.1

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10260 AN: 152130 Hom.: 577 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0778

Gnomad ASJ AF: 0.0897

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0938

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0714

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0674 AC: 10262 AN: 152248 Hom.: 578 Cov.: 32 AF XY: 0.0719 AC XY: 5350 AN XY: 74456

African (AFR) AF: 0.0401 AC: 1667 AN: 41550

American (AMR) AF: 0.0780 AC: 1194 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 311 AN: 3466

East Asian (EAS) AF: 0.320 AC: 1648 AN: 5158

South Asian (SAS) AF: 0.133 AC: 643 AN: 4830

European-Finnish (FIN) AF: 0.0938 AC: 995 AN: 10610

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3609 AN: 68016

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0275 Hom.: 21

Bravo AF: 0.0687

Asia WGS AF: 0.190 AC: 660 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		0.47
PromoterAI		0.067	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2073575; hg19: chr9-35068640;