3-10141782-C-CTCCGCCCCGCG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000551.4(VHL):c.-61_-51dupCCCCGCGTCCG 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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:6B: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]

VHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 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: {Uncertain_significance=5, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000276 (42/152348) while in subpopulation SAS AF = 0.00331 (16/4834). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.-61_-51dupCCCCGCGTCCG	5_prime_UTR_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.-61_-51dupCCCCGCGTCCG	5_prime_UTR_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.-61_-51dupCCCCGCGTCCG	5_prime_UTR_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.10_20dupCCCCGCGTCCG	non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.-61_-51dupCCCCGCGTCCG		5_prime_UTR_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152230

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.000565

AC XY:

381

AN XY:

674038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30530

American (AMR)

AF:

0.000351

AC:

AN:

34140

Ashkenazi Jewish (ASJ)

AF:

0.000446

AC:

AN:

24642

East Asian (EAS)

AF:

0.00

AC:

AN:

35272

South Asian (SAS)

AF:

0.00477

AC:

372

AN:

78024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46076

Middle Eastern (MID)

AF:

0.00623

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.000150

AC:

159

AN:

1056738

Other (OTH)

AF:

0.000689

AC:

AN:

56570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000276

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41584

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00331

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Dec 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The 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. -

Jan 07, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA 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

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VHL: BS1 -

Oct 16, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30006056, 29790589) -

Von Hippel-Lindau syndrome

Uncertain:1

Apr 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant inserts 11 nucleotides in the 5' untranslated region of the VHL gene between c.-52 and c.-51, which overlaps with the minimal VHL promoter defined in a transcription report assay (PMID: 12114475). A carrier of this variant has been shown to have reduced but not fully disrupted VHL expression (PMID: 30006056). This variant has been reported in an individual affected with clear cell renal cell carcinoma and in his unaffected daughter (PMID: 30006056). This variant has been identified in 3/31312 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

VHL-related disorder

Uncertain:1

Mar 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The 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

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 27, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Benign:1

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.94

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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3-10141782-C-CTCCGCCCCGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over