rs373068386

chr3-10142001-G-Achr3-10142001-G-Cchr3-10142001-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_000551.4(VHL):c.154G>A(p.Glu52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,583,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E52E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 1 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8B:5

Conservation

PhyloP100: 0.417

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 312 pathogenic changes around while only 40 benign (89%) in NM_000551.4

BP4

Computational evidence support a benign effect (MetaRNN=0.013942212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VHL	NM_000551.4 linkuse as main transcript	c.154G>A	p.Glu52Lys	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2 linkuse as main transcript	c.154G>A	p.Glu52Lys	missense_variant	1/3
VHL	NM_198156.3 linkuse as main transcript	c.154G>A	p.Glu52Lys	missense_variant	1/2
VHL	NR_176335.1 linkuse as main transcript	n.224G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.154G>A	p.Glu52Lys	missense_variant	1/3	1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000627

AC:

AN:

191496

Hom.:

AF XY:

0.0000571

AC XY:

AN XY:

105086

show subpopulations

Gnomad AFR exome

AF:

0.000703

Gnomad AMR exome

AF:

0.0000688

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000703

Gnomad SAS exome

AF:

0.0000382

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000202

GnomAD4 exome

AF:

0.0000538

AC:

AN:

1430820

Hom.:

Cov.:

AF XY:

0.0000621

AC XY:

AN XY:

709086

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.000100

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000527

Gnomad4 SAS exome

AF:

0.0000363

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000364

Gnomad4 OTH exome

AF:

0.000169

GnomAD4 genome

AF:

0.000197

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000332

ESP6500AA

AF:

0.000715

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000930

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:4Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 20, 2017	- -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 20, 2022	The VHL c.154G>A (p.Glu52Lys) missense change has a maximum subpopulation frequency of 0.075% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with Von Hippel-Lindau disease (PMID: 12202531). In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces glutamic acid with lysine at codon 52 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in families and individuals affected with Von Hippel-Lindau disease (PMID: 12202531, 15300849). This variant has been identified in 19/222880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	VHL: PS4:Moderate -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2021	This variant is associated with the following publications: (PMID: 11257211, 25637381, 27651169, 26211615, 9829912, 24138046, 12202531, 24055113, 21463266, 15300849, 18836774, 19574279, 18416845) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 26, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 18, 2021	- -

Enchondromatosis

Pathogenic:1

Likely pathogenic, flagged submission

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

- -

Hepatoblastoma

Pathogenic:1

Likely pathogenic, flagged submission

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

VHL-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

The VHL c.154G>A variant is predicted to result in the amino acid substitution p.Glu52Lys. This variant has been reported in patients with von Hippel-Lindau disease with and without renal involvement (Dollfus et al. 2002. PubMed ID: 12202531; Supplementary Table S1, Gallou et al. 2004. PubMed ID: 15300849). In addition, this variant has been identified and classified as a variant of uncertain significant in a study analyzing incidental findings in patients of European and African-ancestry that participated in the National Heart, Lung, and Blood Institute Exome Sequencing Project (Supplementary Table 1, Amendola et al. 2015. PubMed ID: 25637381; Supplementary Table 1, Dorschner et al. 2013. PubMed ID: 24055113). This variant has also been reported in an individual with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). However, this variant is reported in 0.075% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183685-G-A), which may be too common to be a primary cause of disease. This variant has interpretations of likely benign, uncertain, and likely pathogenic in ClinVar (ncbi.nlm.nih.gov/clinvar/variation/161402) Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.060

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.76

N;N

REVEL

Uncertain

0.56

Sift4G

Benign

0.21

T;T

Polyphen

0.0010

B;B

Vest4

0.68

MVP

0.93

MPC

0.55

ClinPred

0.012

GERP RS

0.65

Varity_R

0.20

gMVP

0.74

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