Genetic Variant VHL:c.463+43A>G (chr3-10146679-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000551.4(VHL):c.463+43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,610,182 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 32)

Exomes 𝑓: 0.020 ( 371 hom. )

Consequence

VHL
NM_000551.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.232

Publications

7 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

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 3-10146679-A-G is Benign according to our data. Variant chr3-10146679-A-G is described in ClinVar as Benign. ClinVar VariationId is 1244574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1813/152312) while in subpopulation NFE AF = 0.0196 (1330/68028). AF 95% confidence interval is 0.0187. There are 14 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

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.463+43A>G	intron	N/A	NP_000542.1	A0A024R2F2
VHL	NM_001354723.2		c.*18-3108A>G	intron	N/A	NP_001341652.1	A0A8Q3WL21
VHL	NM_198156.3		c.341-3108A>G	intron	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.463+43A>G	intron	N/A	ENSP00000256474.3	P40337-1
VHL	ENST00000345392.3	TSL:1	c.341-3108A>G	intron	N/A	ENSP00000344757.2	P40337-2
VHL	ENST00000477538.2	TSL:1	n.1343+43A>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1811

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00682

Gnomad FIN

AF:

0.00801

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.00958

GnomAD2 exomes

AF:

0.0121

AC:

3047

AN:

251420

AF XY:

0.0125

show subpopulations

Gnomad AFR exome

AF:

0.00339

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00832

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0203

AC:

29539

AN:

1457870

Hom.:

371

Cov.:

AF XY:

0.0198

AC XY:

14362

AN XY:

725264

show subpopulations

African (AFR)

AF:

0.00291

AC:

AN:

33384

American (AMR)

AF:

0.00616

AC:

275

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00661

AC:

172

AN:

26028

East Asian (EAS)

AF:

0.000126

AC:

AN:

39578

South Asian (SAS)

AF:

0.00845

AC:

728

AN:

86180

European-Finnish (FIN)

AF:

0.00908

AC:

482

AN:

53064

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0240

AC:

26663

AN:

1109214

Other (OTH)

AF:

0.0183

AC:

1099

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1382

2764

4145

5527

6909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1030

2060

3090

4120

5150

<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:

0.0119

AC:

1813

AN:

152312

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41582

American (AMR)

AF:

0.00791

AC:

121

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00704

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00801

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0196

AC:

1330

AN:

68028

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

195

292

390

487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0170

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.7

(source)

DANN

Benign

0.68

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over