9-35061506-T-C

Variant names:

• chr9-35061506-T-C
• rs2074549
• NM_007126.5:c.1194+71A>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.1194+71A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 1,397,250 control chromosomes in the GnomAD database, including 5,927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (590 hom., cov: 32)
  • Exomes 𝑓: 0.070 (5337 hom.)
• Consequence: VCP NM_007126.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.156
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-35061506-T-C is Benign according to our data. Variant chr9-35061506-T-C is described in ClinVar as Benign. ClinVar VariationId is 1266224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.1194+71A>G		intron_variant	Intron 10 of 16	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.1059+71A>G		intron_variant	Intron 10 of 16		NP_001341856.1
VCP	NM_001354928.2	c.1059+71A>G		intron_variant	Intron 10 of 16		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.1194+71A>G		intron_variant	Intron 10 of 16	1	NM_007126.5	ENSP00000351777.6

Frequencies

GnomAD3 genomes AF: 0.0694 AC: 10553 AN: 152126 Hom.: 589 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0791

Gnomad ASJ AF: 0.0934

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0931

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0724

GnomAD4 exome AF: 0.0702 AC: 87418 AN: 1245004 Hom.: 5337 AF XY: 0.0720 AC XY: 45375 AN XY: 630348

African (AFR) AF: 0.0460 AC: 1334 AN: 29012

American (AMR) AF: 0.144 AC: 6395 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.0935 AC: 2313 AN: 24738

East Asian (EAS) AF: 0.344 AC: 13323 AN: 38696

South Asian (SAS) AF: 0.119 AC: 9744 AN: 81730

European-Finnish (FIN) AF: 0.0958 AC: 5082 AN: 53030

Middle Eastern (MID) AF: 0.0889 AC: 472 AN: 5312

European-Non Finnish (NFE) AF: 0.0486 AC: 44502 AN: 914854

Other (OTH) AF: 0.0800 AC: 4253 AN: 53184

GnomAD4 genome AF: 0.0694 AC: 10563 AN: 152246 Hom.: 590 Cov.: 32 AF XY: 0.0738 AC XY: 5495 AN XY: 74452

African (AFR) AF: 0.0466 AC: 1936 AN: 41568

American (AMR) AF: 0.0793 AC: 1214 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 324 AN: 3468

East Asian (EAS) AF: 0.321 AC: 1661 AN: 5168

South Asian (SAS) AF: 0.129 AC: 621 AN: 4824

European-Finnish (FIN) AF: 0.0931 AC: 987 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0533 AC: 3623 AN: 68008

Other (OTH) AF: 0.0716 AC: 151 AN: 2108

Alfa AF: 0.0451 Hom.: 61

Bravo AF: 0.0714

Asia WGS AF: 0.190 AC: 660 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.1
DANN	Benign	0.51
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2074549; hg19: chr9-35061503; COSMIC: COSV62719572; COSMIC: COSV62719572;