chr3-10141966-C-T

Position:

chr3-10141966-C-T

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_000551.4(VHL):c.119C>T (p.Pro40Leu) is a missense variant predicted to cause substitution of Proline by Leucine. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0006831 (71/ 84504 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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/CA020046/MONDO:0008667/078

Frequency

Genomes: 𝑓 0.000079 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:6O:1

Conservation

PhyloP100: 0.420

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.119C>T	p.Pro40Leu	missense_variant	1/3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 linkuse as main transcript	c.119C>T	p.Pro40Leu	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.119C>T	p.Pro40Leu	missense_variant	1/2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 linkuse as main transcript	n.189C>T		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.119C>T	p.Pro40Leu	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000263

AC:

AN:

155902

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

84378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000350

Gnomad SAS exome

AF:

0.00155

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.0000620

AC:

AN:

1402306

Hom.:

Cov.:

AF XY:

0.0000708

AC XY:

AN XY:

691960

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.000841

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.000172

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000206

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 09, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 20, 2017	- -
Benign, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The variant NM_000551.4(VHL):c.119C>T (p.Pro40Leu) is a missense variant predicted to cause substitution of Proline by Leucine. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0006831 (71/ 84504 from South Asian Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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). -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28188106, 24728327, 24727139) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 28, 2023	- -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.29

Sift

Uncertain

0.0040

.;D

Sift4G

Benign

0.091

T;T

Polyphen

0.49

P;P

Vest4

0.14

MVP

0.95

MPC

0.84

ClinPred

0.11

GERP RS

3.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.21

gMVP

0.62

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