3-10141900-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000551.4(VHL):c.53C>T(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,379,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -0.344

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
von Hippel-Lindau disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
renal cell carcinoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
autosomal recessive secondary polycythemia not associated with VHL gene
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
Chuvash polycythemia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

VHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049024343).

BP6

Variant 3-10141900-C-T is Benign according to our data. Variant chr3-10141900-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456591.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.53C>T	p.Ala18Val	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.53C>T	p.Ala18Val	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.53C>T	p.Ala18Val	missense_variant	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.123C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.53C>T	p.Ala18Val	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000362

AC:

AN:

1379818

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

678110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30788

American (AMR)

AF:

0.00

AC:

AN:

33948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24332

East Asian (EAS)

AF:

0.0000283

AC:

AN:

35280

South Asian (SAS)

AF:

0.00

AC:

AN:

77302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

0.00000374

AC:

AN:

1069202

Other (OTH)

AF:

0.00

AC:

AN:

56884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:1

May 16, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with valine at codon 18 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has not been identified 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. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the VHL protein (p.Ala18Val). 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. ClinVar contains an entry for this variant (Variation ID: 456591). 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 with a negative predictive value of 95%. 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. -

not provided

Uncertain:1

May 26, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

May 18, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.53C>T (p.A18V) alteration is located in exon 1 (coding exon 1) of the VHL gene. This alteration results from a C to T substitution at nucleotide position 53, causing the alanine (A) at amino acid position 18 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.34

N;N

PhyloP100

-0.34

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.17

Sift

Benign

0.54

.;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0

B;B

Vest4

0.043

MutPred

0.24

Gain of glycosylation at Y23 (P = 0.0012);Gain of glycosylation at Y23 (P = 0.0012);

MVP

0.95

MPC

0.63

ClinPred

0.12

GERP RS

-0.19

PromoterAI

-0.0070

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.058

gMVP

0.34

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over