9-35060305-T-C

Variant names:

• chr9-35060305-T-C
• rs684562
• NM_007126.5:c.1695+8A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007126.5(VCP):​c.1695+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,613,318 control chromosomes in the GnomAD database, including 362,752 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (26017 hom., cov: 33)
  • Exomes 𝑓: 0.67 (336735 hom.)
• Consequence: VCP NM_007126.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003988
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.129
• Publications: 27 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: Orphanet, ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-35060305-T-C is Benign according to our data. Variant chr9-35060305-T-C is described in ClinVar as Benign. ClinVar VariationId is 260124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.703 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.1695+8A>G		splice_region intron	N/A	NP_009057.1	P55072
	VCP	NM_001354927.2		c.1560+8A>G		splice_region intron	N/A	NP_001341856.1	C9JUP7
	VCP	NM_001354928.2		c.1560+8A>G		splice_region intron	N/A	NP_001341857.1	C9JUP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.1695+8A>G		splice_region intron	N/A	ENSP00000351777.6	P55072
	VCP	ENST00000969527.1		c.1695+8A>G		splice_region intron	N/A	ENSP00000639586.1
	VCP	ENST00000940607.1		c.1692+8A>G		splice_region intron	N/A	ENSP00000610666.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 83057 AN: 152050 Hom.: 26006 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.0838

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.587

GnomAD2 exomes AF: 0.592 AC: 148418 AN: 250840 AF XY: 0.596

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.0848

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.640

GnomAD4 exome AF: 0.665 AC: 971828 AN: 1461150 Hom.: 336735 Cov.: 44 AF XY: 0.662 AC XY: 480937 AN XY: 726920

African (AFR) AF: 0.255 AC: 8543 AN: 33462

American (AMR) AF: 0.666 AC: 29756 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 17328 AN: 26130

East Asian (EAS) AF: 0.0688 AC: 2730 AN: 39696

South Asian (SAS) AF: 0.505 AC: 43507 AN: 86234

European-Finnish (FIN) AF: 0.607 AC: 32420 AN: 53402

Middle Eastern (MID) AF: 0.598 AC: 3446 AN: 5764

European-Non Finnish (NFE) AF: 0.717 AC: 796587 AN: 1111408

Other (OTH) AF: 0.621 AC: 37511 AN: 60364

GnomAD4 genome AF: 0.546 AC: 83100 AN: 152168 Hom.: 26017 Cov.: 33 AF XY: 0.540 AC XY: 40184 AN XY: 74398

African (AFR) AF: 0.273 AC: 11332 AN: 41528

American (AMR) AF: 0.659 AC: 10077 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2303 AN: 3470

East Asian (EAS) AF: 0.0839 AC: 435 AN: 5182

South Asian (SAS) AF: 0.481 AC: 2319 AN: 4818

European-Finnish (FIN) AF: 0.606 AC: 6407 AN: 10568

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48181 AN: 67986

Other (OTH) AF: 0.585 AC: 1237 AN: 2116

Alfa AF: 0.651 Hom.: 21283

Bravo AF: 0.536

Asia WGS AF: 0.303 AC: 1059 AN: 3478

EpiCase AF: 0.703

EpiControl AF: 0.703

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (2)
-	-	2	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (2)
-	-	1	Charcot-Marie-Tooth disease type 2Y (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.2
DANN	Benign	0.82
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
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: rs684562; hg19: chr9-35060302; COSMIC: COSV62720360; COSMIC: COSV62720360;