3-10141951-C-T

Position:

chr3-10141951-C-T

Variant summary

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

The NM_000551.4(VHL):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,544,318 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000093 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.144

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 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4

BP4

Computational evidence support a benign effect (MetaRNN=0.1798892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VHL	NM_000551.4 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.104C>T	p.Ala35Val	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1 linkuse as main transcript	n.174C>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.104C>T	p.Ala35Val	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000678

AC:

AN:

147396

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

79122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000447

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000934

AC:

AN:

1392156

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

685612

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000152

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Oct 10, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the VHL protein (p.Ala35Val). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 526678). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2023

The p.A35V variant (also known as c.104C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 104. The alanine at codon 35 is replaced by valine, an amino acid with similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.19

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.013

.;D

Sift4G

Uncertain

0.055

T;T

Polyphen

0.73

P;P

Vest4

0.12

MutPred

0.43

Loss of glycosylation at P40 (P = 0.0446);Loss of glycosylation at P40 (P = 0.0446);

MVP

1.0

MPC

0.63

ClinPred

0.56

GERP RS

3.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.18

gMVP

0.55

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