rs12349922

Positions:

chr9-35061698-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000358901.11(VCP):c.1082-9G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,610,278 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 12 hom. )

Consequence

VCP
ENST00000358901.11 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003090

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0380

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 9-35061698-C-A is Benign according to our data. Variant chr9-35061698-C-A is described in ClinVar as [Benign]. Clinvar id is 464103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35061698-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00613 (932/152130) while in subpopulation AFR AF= 0.0205 (849/41510). AF 95% confidence interval is 0.0193. There are 10 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 932 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
VCP	NM_007126.5 linkuse as main transcript	c.1082-9G>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 linkuse as main transcript	c.947-9G>T	splice_polypyrimidine_tract_variant, intron_variant		NP_001341856.1
VCP	NM_001354928.2 linkuse as main transcript	c.947-9G>T	splice_polypyrimidine_tract_variant, intron_variant		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11 linkuse as main transcript	c.1082-9G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007126.5	ENSP00000351777	P3

Frequencies

GnomAD3 genomes

AF:

0.00612

AC:

930

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00149

AC:

374

AN:

251452

Hom.:

AF XY:

0.00102

AC XY:

139

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000706

AC:

1030

AN:

1458148

Hom.:

Cov.:

AF XY:

0.000599

AC XY:

435

AN XY:

725788

show subpopulations

Gnomad4 AFR exome

AF:

0.0239

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000866

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00613

AC:

932

AN:

152130

Hom.:

Cov.:

AF XY:

0.00582

AC XY:

433

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0205

Gnomad4 AMR

AF:

0.00400

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.00755

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 14, 2020

- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.6

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.034

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over