Genetic Variant VHL:c.-54_-35delTCCGACCCGCGGATCCCGCG (chr3-10141787-CCCCGCGTCCGACCCGCGGAT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000551.4(VHL):c.-54_-35delTCCGACCCGCGGATCCCGCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,372,176 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

VHL
NM_000551.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.-54_-35delTCCGACCCGCGGATCCCGCG	5_prime_UTR_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.-54_-35delTCCGACCCGCGGATCCCGCG	5_prime_UTR_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.-54_-35delTCCGACCCGCGGATCCCGCG	5_prime_UTR_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.17_36delTCCGACCCGCGGATCCCGCG	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.-54_-35delTCCGACCCGCGGATCCCGCG		5_prime_UTR_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1372176

Hom.:

AF XY:

0.00000591

AC XY:

AN XY:

676586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30642

American (AMR)

AF:

0.00

AC:

AN:

34178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24678

East Asian (EAS)

AF:

0.00

AC:

AN:

35310

South Asian (SAS)

AF:

0.00

AC:

AN:

78166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4024

European-Non Finnish (NFE)

AF:

0.00000471

AC:

AN:

1061922

Other (OTH)

AF:

0.00

AC:

AN:

56792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the VHL gene. It does not change the encoded amino acid sequence of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Splicing

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

Publications

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3-10141787-CCCCGCGTCCGACCCGCGGAT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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