Variant rs34661876 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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 links:

VHL (HGNC:):

VHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1244574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10146679-A-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
VHL	NM_000551.4 linkuse as main transcript	c.463+43A>G	intron_variant	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 linkuse as main transcript	c.*18-3108A>G	intron_variant		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.341-3108A>G	intron_variant		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 linkuse as main transcript	n.792+43A>G	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.463+43A>G		intron_variant		1	NM_000551.4	ENSP00000256474.3		P40337-1

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

GnomAD3 exomes

AF:

0.0121

AC:

3047

AN:

251420

Hom.:

AF XY:

0.0125

AC XY:

1698

AN XY:

135882

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 SAS exome

AF:

0.00830

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

Gnomad4 AFR exome

AF:

0.00291

Gnomad4 AMR exome

AF:

0.00616

Gnomad4 ASJ exome

AF:

0.00661

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00845

Gnomad4 FIN exome

AF:

0.00908

Gnomad4 NFE exome

AF:

0.0240

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0119

AC:

1813

AN:

152312

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00414

Gnomad4 AMR

AF:

0.00791

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.00801

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.7

DANN

Benign

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over