chr9-35056081-G-GT

Position:

• chr9-35056081-G-GT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_007126.5(VCP):​c.*1035_*1036insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 144,312 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.019 (75 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: VCP NM_007126.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.839

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCP	NM_007126.5	c.*1035_*1036insA		3_prime_UTR_variant	17/17	ENST00000358901.11
VCP	NM_001354927.2	c.*1035_*1036insA		3_prime_UTR_variant	17/17
VCP	NM_001354928.2	c.*1035_*1036insA		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCP	ENST00000358901.11	c.*1035_*1036insA		3_prime_UTR_variant	17/17	1	NM_007126.5	P3

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2810 AN: 144262 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.00827

Gnomad ASJ AF: 0.000598

Gnomad EAS AF: 0.000400

Gnomad SAS AF: 0.00306

Gnomad FIN AF: 0.00582

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0118

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0195 AC: 2809 AN: 144312 Hom.: 75 Cov.: 32 AF XY: 0.0184 AC XY: 1285 AN XY: 69888

Gnomad4 AFR AF: 0.0635

Gnomad4 AMR AF: 0.00826

Gnomad4 ASJ AF: 0.000598

Gnomad4 EAS AF: 0.000401

Gnomad4 SAS AF: 0.00241

Gnomad4 FIN AF: 0.00582

Gnomad4 NFE AF: 0.00130

Gnomad4 OTH AF: 0.0117

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic Lateral Sclerosis, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inclusion Body Myopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs532528005; hg19: chr9-35056078;