9-35061172-T-C

Position:

chr9-35061172-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BS1BS2

The NM_007126.5(VCP):c.1202A>G(p.Asn401Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

VCP
NM_007126.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 8.02

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:

VCP (HGNC:):

VCP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCP. . Gene score misZ 5.4064 (greater than the threshold 3.09). Trascript score misZ 8.1614 (greater than threshold 3.09). GenCC has associacion of gene with spastic paraplegia-Paget disease of bone syndrome, adult-onset distal myopathy due to VCP mutation, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, Charcot-Marie-Tooth disease type 2Y, amyotrophic lateral sclerosis, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, frontotemporal dementia with motor neuron disease, inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000138 (21/152298) while in subpopulation SAS AF= 0.00104 (5/4830). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VCP	NM_007126.5 linkuse as main transcript	c.1202A>G	p.Asn401Ser	missense_variant	11/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 linkuse as main transcript	c.1067A>G	p.Asn356Ser	missense_variant	11/17		NP_001341856.1
VCP	NM_001354928.2 linkuse as main transcript	c.1067A>G	p.Asn356Ser	missense_variant	11/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11 linkuse as main transcript	c.1202A>G	p.Asn401Ser	missense_variant	11/17	1	NM_007126.5	ENSP00000351777.6		P55072

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251264

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000170

AC:

248

AN:

1460984

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00188

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000138

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	This variant is associated with the following publications: (PMID: 27990419, 32403337, 27439681) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

VCP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.14

Eigen_PC

Benign

0.096

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.022

MutationAssessor

Benign

-0.11

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.29

REVEL

Uncertain

0.30

Sift

Benign

0.35

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.83

MVP

0.75

MPC

1.1

ClinPred

0.029

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.43

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 3

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