chr3-10141653-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000551.4(VHL):c.-195G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 598,664 control chromosomes in the GnomAD database, including 129,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene VHL is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.57 ( 27770 hom., cov: 33)

Exomes 𝑓: 0.67 ( 102174 hom. )

Consequence

VHL
NM_000551.4 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.395

Publications

42 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
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

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 3-10141653-G-A is Benign according to our data. Variant chr3-10141653-G-A is described in ClinVar as Benign. ClinVar VariationId is 342397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VHL	NM_000551.4	MANE Select	c.-195G>A	upstream_gene	N/A	NP_000542.1	A0A024R2F2
VHL	NM_001354723.2		c.-195G>A	upstream_gene	N/A	NP_001341652.1	A0A8Q3WL21
VHL	NM_198156.3		c.-195G>A	upstream_gene	N/A	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VHL	ENST00000256474.3	TSL:1 MANE Select	c.-195G>A	upstream_gene	N/A	ENSP00000256474.3	P40337-1
VHL	ENST00000345392.3	TSL:1	c.-195G>A	upstream_gene	N/A	ENSP00000344757.2	P40337-2
VHL	ENST00000477538.2	TSL:1	n.-149G>A	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.569

AC:

86405

AN:

151902

Hom.:

27755

Cov.:

show subpopulations

Gnomad AFR

AF:

0.243

Gnomad AMI

AF:

0.602

Gnomad AMR

AF:

0.652

Gnomad ASJ

AF:

0.740

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.761

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.692

Gnomad OTH

AF:

0.605

GnomAD4 exome

AF:

0.670

AC:

299218

AN:

446648

Hom.:

102174

Cov.:

AF XY:

0.664

AC XY:

155049

AN XY:

233610

show subpopulations

African (AFR)

AF:

0.252

AC:

2345

AN:

9314

American (AMR)

AF:

0.642

AC:

9405

AN:

14642

Ashkenazi Jewish (ASJ)

AF:

0.736

AC:

9418

AN:

12802

East Asian (EAS)

AF:

0.734

AC:

19672

AN:

26808

South Asian (SAS)

AF:

0.544

AC:

23846

AN:

43836

European-Finnish (FIN)

AF:

0.749

AC:

22116

AN:

29534

Middle Eastern (MID)

AF:

0.624

AC:

1200

AN:

1922

European-Non Finnish (NFE)

AF:

0.689

AC:

194551

AN:

282216

Other (OTH)

AF:

0.652

AC:

16665

AN:

25574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

5183

10367

15550

20734

25917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1240

2480

3720

4960

6200

<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

AF:

0.569

AC:

86449

AN:

152016

Hom.:

27770

Cov.:

AF XY:

0.576

AC XY:

42806

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.244

AC:

10098

AN:

41460

American (AMR)

AF:

0.652

AC:

9975

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.740

AC:

2571

AN:

3472

East Asian (EAS)

AF:

0.788

AC:

4069

AN:

5162

South Asian (SAS)

AF:

0.558

AC:

2690

AN:

4820

European-Finnish (FIN)

AF:

0.761

AC:

8012

AN:

10530

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.692

AC:

47025

AN:

67972

Other (OTH)

AF:

0.599

AC:

1262

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1632

3264

4897

6529

8161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.644

Hom.:

40256

Bravo

AF:

0.548

Asia WGS

AF:

0.655

AC:

2277

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary cancer-predisposing syndrome (1)

Von Hippel-Lindau syndrome (1)

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.3

(source)

DANN

Benign

0.82

PhyloP100

0.40

PromoterAI

-0.081

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over