NM_000551.4:c.163dupG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000551.4(VHL):c.163dupG(p.Glu55GlyfsTer77) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E55E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
VHL
NM_000551.4 frameshift
NM_000551.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.15
Publications
3 publications found
Genes affected
VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]
VHL Gene-Disease associations (from GenCC):
- pheochromocytomaInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- von Hippel-Lindau diseaseInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
- renal cell carcinomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- autosomal recessive secondary polycythemia not associated with VHL geneInheritance: AR Classification: STRONG Submitted by: Ambry Genetics
- Chuvash polycythemiaInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-10142008-T-TG is Pathogenic according to our data. Variant chr3-10142008-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 223159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | MANE Select | c.163dupG | p.Glu55GlyfsTer77 | frameshift | Exon 1 of 3 | NP_000542.1 | ||
| VHL | NM_001354723.2 | c.163dupG | p.Glu55GlyfsTer127 | frameshift | Exon 1 of 3 | NP_001341652.1 | |||
| VHL | NM_198156.3 | c.163dupG | p.Glu55GlyfsTer78 | frameshift | Exon 1 of 2 | NP_937799.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| VHL | ENST00000256474.3 | TSL:1 MANE Select | c.163dupG | p.Glu55GlyfsTer77 | frameshift | Exon 1 of 3 | ENSP00000256474.3 | ||
| VHL | ENST00000345392.3 | TSL:1 | c.163dupG | p.Glu55GlyfsTer78 | frameshift | Exon 1 of 2 | ENSP00000344757.2 | ||
| VHL | ENST00000477538.2 | TSL:1 | n.209dupG | non_coding_transcript_exon | Exon 1 of 3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.97e-7 AC: 1AN: 1435340Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 711842 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1435340
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
711842
show subpopulations
African (AFR)
AF:
AC:
0
AN:
32904
American (AMR)
AF:
AC:
0
AN:
40770
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25544
East Asian (EAS)
AF:
AC:
0
AN:
38250
South Asian (SAS)
AF:
AC:
0
AN:
83044
European-Finnish (FIN)
AF:
AC:
0
AN:
49296
Middle Eastern (MID)
AF:
AC:
0
AN:
5590
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1100612
Other (OTH)
AF:
AC:
0
AN:
59330
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Hereditary cancer-predisposing syndrome (1)
1
-
-
Von Hippel-Lindau syndrome (1)
1
-
-
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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