3-10141782-CTCCGCCCCGCG-CTCCGCCCCGCGTCCGCCCCGCG

Variant names:

• chr3-10141782-C-CTCCGCCCCGCG
• rs727503743
• NM_000551.4:c.-61_-51dupCCCCGCGTCCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: -0.938

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]

ACMG classification

Verdict is Benign. Variant got -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: {Likely_benign=3, Uncertain_significance=4}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.-61_-51dupCCCCGCGTCCG		5_prime_UTR_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.-61_-51dupCCCCGCGTCCG		5_prime_UTR_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.-61_-51dupCCCCGCGTCCG		5_prime_UTR_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	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	c.-61_-51dupCCCCGCGTCCG		5_prime_UTR_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152230 Hom.: 0 Cov.: 33

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

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

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:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

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. -

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. -

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) -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503743; hg19: chr3-10183466;