3-10142014-C-G

Position:

chr3-10142014-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The ENST00000256474.3(VHL):c.167C>G(p.Ala56Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,589,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

VHL
ENST00000256474.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.353

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in ENST00000256474.3

BP4

Computational evidence support a benign effect (MetaRNN=0.14638096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VHL	NM_000551.4 linkuse as main transcript	c.167C>G	p.Ala56Gly	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2 linkuse as main transcript	c.167C>G	p.Ala56Gly	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.167C>G	p.Ala56Gly	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1 linkuse as main transcript	n.237C>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.167C>G	p.Ala56Gly	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000997

AC:

AN:

200656

Hom.:

AF XY:

0.0000181

AC XY:

AN XY:

110422

show subpopulations

Gnomad AFR exome

AF:

0.0000937

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000299

AC:

AN:

1437454

Hom.:

Cov.:

AF XY:

0.0000351

AC XY:

AN XY:

713182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000910

Gnomad4 AMR exome

AF:

0.0000243

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000345

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000571

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000844

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or erythrocytosis in published literature (Oliveira et al., 2018; McDonald et al., 2022); This variant is associated with the following publications: (PMID: 29790589, 35142155, 36315513) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2023	The p.A56G variant (also known as c.167C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 167. The alanine at codon 56 is replaced by glycine, an amino acid with similar properties. This variant has been reported in a thrombosis patient who underwent hereditary erythrocytosis multi-gene panel testing (Oliveira JL et al. Am J Hematol. 2018 May 23). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 27, 2021	- -

Von Hippel-Lindau syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 04, 2015

- -

Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 21, 2024

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 01, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 56 of the VHL protein (p.Ala56Gly). This variant is present in population databases (rs752980085, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 371800). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.11

Sift

Benign

0.17

.;T

Sift4G

Benign

0.37

T;T

Polyphen

0.079

B;B

Vest4

0.056

MutPred

0.23

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);

MVP

0.96

MPC

0.55

ClinPred

0.089

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.79

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