rs1642742

Variant names:

• chr3-10150259-G-A
• rs1642742
• ENST00000477538.2:n.1816G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10150259-G-A
• chr3-10150259-G-C
• chr3-10150259-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000477538.2(VHL):​n.1816G>A variant causes a non coding transcript exon 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 ENST00000477538.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.519
• Publications: 52 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287086 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.*294G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NR_176335.1	n.1265G>A		non_coding_transcript_exon_variant	Exon 4 of 4
VHL	NM_001354723.2	c.*490G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NM_198156.3	c.*294G>A		3_prime_UTR_variant	Exon 2 of 2		NP_937799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.*294G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3

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

African (AFR) AF: 0.263 AC: 6850 AN: 26008

American (AMR) AF: 0.654 AC: 10245 AN: 15662

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 11572 AN: 15794

East Asian (EAS) AF: 0.755 AC: 19108 AN: 25300

South Asian (SAS) AF: 0.549 AC: 32514 AN: 59248

European-Finnish (FIN) AF: 0.742 AC: 9880 AN: 13310

Middle Eastern (MID) AF: 0.617 AC: 1833 AN: 2970

European-Non Finnish (NFE) AF: 0.683 AC: 648770 AN: 950328

Other (OTH) AF: 0.657 AC: 30218 AN: 45998

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

African (AFR) AF: 0.289 AC: 11978 AN: 41450

American (AMR) AF: 0.656 AC: 10010 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2570 AN: 3466

East Asian (EAS) AF: 0.788 AC: 4069 AN: 5164

South Asian (SAS) AF: 0.556 AC: 2687 AN: 4830

European-Finnish (FIN) AF: 0.760 AC: 8019 AN: 10556

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46746 AN: 67948

Other (OTH) AF: 0.605 AC: 1276 AN: 2110

Alfa AF: 0.654 Hom.: 136934

Bravo AF: 0.560

Asia WGS AF: 0.652 AC: 2269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Von Hippel-Lindau syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.28
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1642742; hg19: chr3-10191943;