rs142577424

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-35059793-T-C
• chr9-35059793-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007126.5(VCP):​c.1704A>G​(p.Gln568Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,614,084 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (6 hom.)
• Consequence: VCP NM_007126.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-35059793-T-C is Benign according to our data. Variant chr9-35059793-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.752 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00296 (451/152194) while in subpopulation AMR AF = 0.00727 (111/15268). AF 95% confidence interval is 0.00617. There are 4 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 451 AD gene.

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.1704A>G	p.Gln568Gln	synonymous	Exon 14 of 17	NP_009057.1	P55072
	VCP	NM_001354927.2		c.1569A>G	p.Gln523Gln	synonymous	Exon 14 of 17	NP_001341856.1	C9JUP7
	VCP	NM_001354928.2		c.1569A>G	p.Gln523Gln	synonymous	Exon 14 of 17	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.1704A>G	p.Gln568Gln	synonymous	Exon 14 of 17	ENSP00000351777.6	P55072
	VCP	ENST00000479300.2	TSL:1	n.232A>G		non_coding_transcript_exon	Exon 1 of 4
	VCP	ENST00000969527.1		c.1797A>G	p.Gln599Gln	synonymous	Exon 15 of 18	ENSP00000639586.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 451 AN: 152076 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00728

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00274 AC: 685 AN: 250400 AF XY: 0.00258

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.00439

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00366 AC: 5346 AN: 1461890 Hom.: 6 Cov.: 32 AF XY: 0.00355 AC XY: 2585 AN XY: 727246

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000614 AC: 53 AN: 86258

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00434 AC: 4822 AN: 1112008

Other (OTH) AF: 0.00353 AC: 213 AN: 60396

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152194 Hom.: 4 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74418

African (AFR) AF: 0.000867 AC: 36 AN: 41526

American (AMR) AF: 0.00727 AC: 111 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00337

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (1)
-	-	1	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)
-	-	1	VCP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;