3-10142030-C-G

Position:

chr3-10142030-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.183C>G (p.Pro61=) is a silent variant in the first exon of VHL. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001902 (192/89258 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020075/MONDO:0008667/078

Frequency

Genomes: 𝑓 0.00076 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

VHL
NM_000551.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11

Conservation

PhyloP100: -1.76

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:

VHL (HGNC:):

VHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4 linkuse as main transcript	c.183C>G	p.Pro61Pro	synonymous_variant	1/3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 linkuse as main transcript	c.183C>G	p.Pro61Pro	synonymous_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.183C>G	p.Pro61Pro	synonymous_variant	1/2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 linkuse as main transcript	n.253C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.183C>G	p.Pro61Pro	synonymous_variant	1/3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

116

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00101

AC:

216

AN:

214678

Hom.:

AF XY:

0.00113

AC XY:

134

AN XY:

118510

show subpopulations

Gnomad AFR exome

AF:

0.000167

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.000309

Gnomad SAS exome

AF:

0.00240

Gnomad FIN exome

AF:

0.0000576

Gnomad NFE exome

AF:

0.000868

Gnomad OTH exome

AF:

0.000938

GnomAD4 exome

AF:

0.00102

AC:

1473

AN:

1446364

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

762

AN XY:

718518

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.00147

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.000103

Gnomad4 SAS exome

AF:

0.00214

Gnomad4 FIN exome

AF:

0.0000813

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.000820

GnomAD4 genome

AF:

0.000761

AC:

116

AN:

152356

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000528

Hom.:

Bravo

AF:

0.000937

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	VHL: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2022	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Von Hippel-Lindau syndrome

Benign:2

Benign, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The variant NM_000551.3(VHL):c.183C>G (p.Pro61=) is a silent variant in the first exon of VHL. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001902 (192/89258 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 17, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.9

DANN

Benign

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over