rs3087462

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000551.4(VHL):c.-77C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,488,092 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.026 ( 188 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 144 hom. )

Consequence

VHL
NM_000551.4 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.67

Publications

2 publications found

Variant links:

COSMIC-nc: COSV104558409

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.-77C>T	upstream_gene_variant	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.-77C>T	upstream_gene_variant		NP_001341652.1
VHL	NM_198156.3 link	c.-77C>T	upstream_gene_variant		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.-7C>T	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.-77C>T		upstream_gene_variant		1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0261

AC:

3972

AN:

152214

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0908

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0224

GnomAD4 exome

AF:

0.00251

AC:

3348

AN:

1335762

Hom.:

144

Cov.:

AF XY:

0.00218

AC XY:

1439

AN XY:

660436

show subpopulations

African (AFR)

AF:

0.0906

AC:

2700

AN:

29806

American (AMR)

AF:

0.00515

AC:

174

AN:

33770

Ashkenazi Jewish (ASJ)

AF:

0.0000410

AC:

AN:

24366

East Asian (EAS)

AF:

0.00

AC:

AN:

35042

South Asian (SAS)

AF:

0.0000388

AC:

AN:

77368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45034

Middle Eastern (MID)

AF:

0.00229

AC:

AN:

3936

European-Non Finnish (NFE)

AF:

0.000137

AC:

141

AN:

1030890

Other (OTH)

AF:

0.00576

AC:

320

AN:

55550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

161

323

484

646

807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0261

AC:

3978

AN:

152330

Hom.:

188

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0907

AC:

3771

AN:

41564

American (AMR)

AF:

0.00954

AC:

146

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.0222

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

188

376

563

751

939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0181

Hom.:

Bravo

AF:

0.0306

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 23, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Von Hippel-Lindau syndrome

Benign:1

Feb 02, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

1.7

PromoterAI

-0.029

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs3087462

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over