3-10141787-C-CCCCGCGTCCGACCCGCGGAT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000551.4(VHL):c.-54_-35dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VHL NM_000551.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.552

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-10141787-C-CCCCGCGTCCGACCCGCGGAT is Benign according to our data. Variant chr3-10141787-C-CCCCGCGTCCGACCCGCGGAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182985.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.-54_-35dup		5_prime_UTR_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.-54_-35dup		5_prime_UTR_variant	1/3
VHL	NM_198156.3	c.-54_-35dup		5_prime_UTR_variant	1/2
VHL	NR_176335.1	n.17_36dup		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.-54_-35dup		5_prime_UTR_variant	1/3	1	NM_000551.4	P1
VHL	ENST00000696153.1	c.-54_-35dup		5_prime_UTR_variant	1/4
VHL	ENST00000696142.1	c.-54_-35dup		5_prime_UTR_variant, NMD_transcript_variant	1/4
VHL	ENST00000345392.2			upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372178 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 676586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2014

This duplication of 20 nucleotides is denoted VHL c.-35_-34insTCCGACCCGCGGATCCCGCG (aka c.-54_-35dup20), and describes a duplication upstream of the VHL ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence is CGCG{dup20}GCGT. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism and does not appear to affect the start codon or the Kozak translational consensus sequence. At this time, we consider VHL c.-54_-35dup20 to be a variant of unknown significance. The variant is found in MODRISK-HEREDICV3 panel(s). -

VHL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs730882036; hg19: chr3-10183471;