rs1642742

chr3-10150259-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000551.4(VHL):c.*294G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 1,306,604 control chromosomes in the GnomAD database, including 288,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28081 hom., cov: 31)
  • Exomes 𝑓: 0.67 (260708 hom.)
• Consequence: VHL NM_000551.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.519

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-10150259-G-A is Benign according to our data. Variant chr3-10150259-G-A is described in ClinVar as [Benign]. Clinvar id is 342407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.*294G>A		3_prime_UTR_variant	3/3	ENST00000256474.3
VHL	NM_001354723.2	c.*490G>A		3_prime_UTR_variant	3/3
VHL	NM_198156.3	c.*294G>A		3_prime_UTR_variant	2/2
VHL	NR_176335.1	n.1265G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.*294G>A		3_prime_UTR_variant	3/3	1	NM_000551.4	P1
	ENST00000660063.1	n.900C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88059 AN: 151868 Hom.: 28070 Cov.: 31

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.612

GnomAD4 exome AF: 0.668 AC: 770990 AN: 1154618 Hom.: 260708 Cov.: 45 AF XY: 0.665 AC XY: 368627 AN XY: 554038

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.654

Gnomad4 ASJ exome AF: 0.733

Gnomad4 EAS exome AF: 0.755

Gnomad4 SAS exome AF: 0.549

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.657

GnomAD4 genome AF: 0.580 AC: 88099 AN: 151986 Hom.: 28081 Cov.: 31 AF XY: 0.587 AC XY: 43592 AN XY: 74304

Gnomad4 AFR AF: 0.289

Gnomad4 AMR AF: 0.656

Gnomad4 ASJ AF: 0.741

Gnomad4 EAS AF: 0.788

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.760

Gnomad4 NFE AF: 0.688

Gnomad4 OTH AF: 0.605

Alfa AF: 0.673 Hom.: 65133

Bravo AF: 0.560

Asia WGS AF: 0.652 AC: 2269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.6
Dann	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1642742; hg19: chr3-10191943;