rs773519476

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_000551.4(VHL):c.135G>A(p.Pro45Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000957 in 1,567,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P45P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

VHL
NM_000551.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.02

Publications

0 publications found

Variant links:

COSMIC-nc: COSV56572910

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 3-10141982-G-A is Benign according to our data. Variant chr3-10141982-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.02 with no splicing effect.

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
VHL	NM_000551.4	MANE Select	c.135G>A	p.Pro45Pro	synonymous	Exon 1 of 3	NP_000542.1
VHL	NM_001354723.2		c.135G>A	p.Pro45Pro	synonymous	Exon 1 of 3	NP_001341652.1
VHL	NM_198156.3		c.135G>A	p.Pro45Pro	synonymous	Exon 1 of 2	NP_937799.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VHL	ENST00000256474.3	TSL:1 MANE Select	c.135G>A	p.Pro45Pro	synonymous	Exon 1 of 3	ENSP00000256474.3
VHL	ENST00000345392.3	TSL:1	c.135G>A	p.Pro45Pro	synonymous	Exon 1 of 2	ENSP00000344757.2
VHL	ENST00000477538.2	TSL:1	n.181G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000586

AC:

AN:

170508

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000118

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000353

AC:

AN:

1415028

Hom.:

Cov.:

AF XY:

0.00000429

AC XY:

AN XY:

699656

show subpopulations

African (AFR)

AF:

0.0000931

AC:

AN:

32232

American (AMR)

AF:

0.00

AC:

AN:

37474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25274

East Asian (EAS)

AF:

0.00

AC:

AN:

36908

South Asian (SAS)

AF:

0.00

AC:

AN:

80922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089704

Other (OTH)

AF:

0.0000341

AC:

AN:

58626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41468

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Von Hippel-Lindau syndrome (3)

Hereditary cancer-predisposing syndrome (2)

not provided (1)

VHL-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

3.3

(source)

DANN

Benign

0.90

PhyloP100

-2.0

PromoterAI

0.077

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over