3-10141782-CTCCGCCCCGCG-CTCCGCCCCGCGTCCGCCCCGCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_000551.4(VHL):​c.-61_-51dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,518,350 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00045 ( 7 hom. )

Consequence

VHL
NM_000551.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: -0.938
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6
Variant 3-10141782-C-CTCCGCCCCGCG is Benign according to our data. Variant chr3-10141782-C-CTCCGCCCCGCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517152.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
BS2
High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VHLNM_000551.4 linkuse as main transcriptc.-61_-51dup 5_prime_UTR_variant 1/3 ENST00000256474.3
VHLNM_001354723.2 linkuse as main transcriptc.-61_-51dup 5_prime_UTR_variant 1/3
VHLNM_198156.3 linkuse as main transcriptc.-61_-51dup 5_prime_UTR_variant 1/2
VHLNR_176335.1 linkuse as main transcriptn.10_20dup non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.-61_-51dup 5_prime_UTR_variant 1/31 NM_000551.4 P1P40337-1
VHLENST00000696153.1 linkuse as main transcriptc.-61_-51dup 5_prime_UTR_variant 1/4
VHLENST00000345392.2 linkuse as main transcript upstream_gene_variant 1 P40337-2
VHLENST00000696142.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
AF:
0.000282
AC:
43
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00331
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000294
Gnomad OTH
AF:
0.000478
GnomAD4 exome
AF:
0.000452
AC:
618
AN:
1366002
Hom.:
7
Cov.:
29
AF XY:
0.000565
AC XY:
381
AN XY:
674038
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000351
Gnomad4 ASJ exome
AF:
0.000446
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00477
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000150
Gnomad4 OTH exome
AF:
0.000689
GnomAD4 genome
AF:
0.000276
AC:
42
AN:
152348
Hom.:
0
Cov.:
33
AF XY:
0.000336
AC XY:
25
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00331
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000294
Gnomad4 OTH
AF:
0.000473

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 10, 2014The c.-61_-51dup variant in VHL has previously been identified by our laboratory in 1 individual with VHL. Data from large population studies is insufficient to assess the frequency of this variant. This variant is located in the 5' untrans lated region (UTR) and variants in regulatory regions could have an effect on tr anscriptional or translational efficiency. Studies have shown that sequence alte rations in this region may alter VHL transcription (Zatyka 2002) and our laborat ory has identified a 5' UTR deletion variant in VHL overlapping with this region that segregated with disease in multiple affected individuals (LMM unpublished data). However, in the absence of additional information, further data is needed to fully assess the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 07, 2021DNA sequence analysis of the VHL gene demonstrated an 11 base pair duplication in the 5' untranslated region, c.-61_-51dup. This change has been previously described in an individual with a single renal cyst and his apparently asymptomatic daughter, both of whom did not fulfill clinical diagnostic criteria of VHL-related disorder (PMID: 30006056). Western blotting and VHL transcript analysis showed milder reduction of VHL gene expression. This sequence change has been described in the gnomAD with a low population frequency of 0.0096% (dbSNP rs529928317). The functional significance of this sequence change is not clearly established at present and its contribution to this patient's disease phenotype cannot definitively be determined. -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 16, 2019This variant is associated with the following publications: (PMID: 30006056, 29790589) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023VHL: BS1 -
VHL-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 18, 2024The VHL c.-61_-51dup11 variant is located in the 5' untranslated region. This variant has been reported in individuals with erythrocytosis (Table 2, Oliveira et al. 2018. PubMed ID: 29790589) and an individual with suspected Von Hippel-Lindau disease (Albanyan et al. 2018. PubMed ID: 30006056). RT-QPCR analysis revealed a modest reduction in RNA (61%) and protein (77%) expression in patient-derived fibroblasts compared to a healthy control (Albanyan et al. 2018. PubMed ID: 30006056). This variant is reported in 3 of ~31,000 alleles in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/517152/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 04, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Nov 27, 2021- -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 04, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs727503743; hg19: chr3-10183466; API