rs34097935
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_007126.5(VCP):c.927C>T(p.Ile309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,614,082 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0024 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 2 hom. )
Consequence
VCP
NM_007126.5 synonymous
NM_007126.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0480
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
Variant 9-35062235-G-A is Benign according to our data. Variant chr9-35062235-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 366719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.048 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00244 (371/152194) while in subpopulation AFR AF= 0.00824 (342/41520). AF 95% confidence interval is 0.00752. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 371 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCP | NM_007126.5 | c.927C>T | p.Ile309= | synonymous_variant | 8/17 | ENST00000358901.11 | |
VCP | NM_001354927.2 | c.792C>T | p.Ile264= | synonymous_variant | 8/17 | ||
VCP | NM_001354928.2 | c.792C>T | p.Ile264= | synonymous_variant | 8/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCP | ENST00000358901.11 | c.927C>T | p.Ile309= | synonymous_variant | 8/17 | 1 | NM_007126.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00244 AC: 371AN: 152076Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000589 AC: 148AN: 251450Hom.: 0 AF XY: 0.000478 AC XY: 65AN XY: 135904
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GnomAD4 exome AF: 0.000311 AC: 455AN: 1461888Hom.: 2 Cov.: 32 AF XY: 0.000287 AC XY: 209AN XY: 727246
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GnomAD4 genome ? AF: 0.00244 AC: 371AN: 152194Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177AN XY: 74412
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 19, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 05, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | VCP: BP4, BP7, BS1 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2017 | - - |
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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 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. - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 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. - |
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 | Invitae | Jan 26, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at