3-10141850-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_StrongBP6

The NM_000551.4(VHL):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,535,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene VHL is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

VHL
NM_000551.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.0460

Publications

16 publications found

Variant links:

COSMIC-nc: COSV99078436

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: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 54 codons. Genomic position: 10142007. Lost 0.249 part of the original CDS.

BP6

Variant 3-10141850-G-T is Benign according to our data. Variant chr3-10141850-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238106.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
VHL	NM_000551.4	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 3	NP_000542.1	A0A024R2F2
VHL	NM_001354723.2		c.3G>T	p.Met1?	start_lost	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
VHL	NM_198156.3		c.3G>T	p.Met1?	start_lost	Exon 1 of 2	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VHL	ENST00000256474.3	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 3	ENSP00000256474.3	P40337-1
VHL	ENST00000345392.3	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 1 of 2	ENSP00000344757.2	P40337-2
VHL	ENST00000477538.2	TSL:1	n.49G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000575

AC:

AN:

139020

AF XY:

0.0000538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000945

Gnomad FIN exome

AF:

0.000205

Gnomad NFE exome

AF:

0.0000588

Gnomad OTH exome

AF:

0.000250

GnomAD4 exome

AF:

0.0000448

AC:

AN:

1383052

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

680752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30844

American (AMR)

AF:

0.0000890

AC:

AN:

33694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24472

East Asian (EAS)

AF:

0.0000848

AC:

AN:

35366

South Asian (SAS)

AF:

0.0000128

AC:

AN:

77868

European-Finnish (FIN)

AF:

0.000105

AC:

AN:

47818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

0.0000401

AC:

AN:

1071872

Other (OTH)

AF:

0.000123

AC:

AN:

57096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

AF:

0.0000591

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41594

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000447

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Von Hippel-Lindau syndrome (2)

not specified (1)

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.39

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.63

PhyloP100

0.046

PROVEAN

Benign

-0.46

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.22

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0604)

MVP

0.85

ClinPred

0.50

GERP RS

0.18

PromoterAI

-0.061

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.64

gMVP

0.54

Mutation Taster

=98/102

disease causing

(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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over