3-10141854-C-T

Position:

chr3-10141854-C-T

Variant summary

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

The ENST00000256474.3(VHL):c.7C>T(p.Arg3Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,535,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. R3G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

VHL
ENST00000256474.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.73

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 chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 311 pathogenic changes around while only 52 benign (86%) in ENST00000256474.3

BP4

Computational evidence support a benign effect (MetaRNN=0.08868858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VHL	NM_000551.4 linkuse as main transcript	c.7C>T	p.Arg3Trp	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2 linkuse as main transcript	c.7C>T	p.Arg3Trp	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.7C>T	p.Arg3Trp	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1 linkuse as main transcript	n.77C>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.7C>T	p.Arg3Trp	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000362

AC:

AN:

1383062

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

680562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000294

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:

0.00000280

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VHL protein function. 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. ClinVar contains an entry for this variant (Variation ID: 238114). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3 of the VHL protein (p.Arg3Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2022

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 a patient with early onset colorectal cancer and no family history (Thutkawkorapin et al., 2019); This variant is associated with the following publications: (PMID: 30809968) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The p.R3W variant (also known as c.7C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 7. The arginine at codon 3 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.61

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.20

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.16

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0030

B;B

Vest4

0.12

MutPred

0.33

Gain of catalytic residue at R3 (P = 0.0368);Gain of catalytic residue at R3 (P = 0.0368);

MVP

0.83

MPC

0.82

ClinPred

0.45

GERP RS

-2.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.14

gMVP

0.40

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