3-10142192-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000551.4(VHL):c.340+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,596,998 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 190 hom. )

Consequence

VHL
NM_000551.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9553

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 2.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 3-10142192-G-C is Benign according to our data. Variant chr3-10142192-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 36901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142192-G-C is described in Lovd as [Likely_benign]. Variant chr3-10142192-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
VHL	NM_000551.4 linkuse as main transcript	c.340+5G>C	splice_donor_5th_base_variant, intron_variant	ENST00000256474.3
VHL	NM_001354723.2 linkuse as main transcript	c.340+5G>C	splice_donor_5th_base_variant, intron_variant
VHL	NM_198156.3 linkuse as main transcript	c.340+5G>C	splice_donor_5th_base_variant, intron_variant
VHL	NR_176335.1 linkuse as main transcript	n.410+5G>C	splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.340+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

610

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0585

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.0125

AC:

2715

AN:

217310

Hom.:

AF XY:

0.0138

AC XY:

1672

AN XY:

121436

show subpopulations

Gnomad AFR exome

AF:

0.000390

Gnomad AMR exome

AF:

0.0206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0254

Gnomad SAS exome

AF:

0.0503

Gnomad FIN exome

AF:

0.000270

Gnomad NFE exome

AF:

0.000481

Gnomad OTH exome

AF:

0.00669

GnomAD4 exome

AF:

0.00460

AC:

6648

AN:

1444702

Hom.:

190

Cov.:

AF XY:

0.00583

AC XY:

4191

AN XY:

718988

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0197

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.0201

Gnomad4 SAS exome

AF:

0.0496

Gnomad4 FIN exome

AF:

0.000261

Gnomad4 NFE exome

AF:

0.000268

Gnomad4 OTH exome

AF:

0.00617

GnomAD4 genome

AF:

0.00400

AC:

609

AN:

152296

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

384

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00942

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0249

Gnomad4 SAS

AF:

0.0579

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000856

Hom.:

Bravo

AF:

0.00371

Asia WGS

AF:

0.0270

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2013	340+5G>C in intron 1 of VHL: This variant is not expected to have clinical signi ficance because it has been identified in 4.5% (9/200) Southern Han Chinese chro mosomes by the 1000 Genomes Project (dbSNP rs61758376). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Von Hippel-Lindau syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 21, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2018	This variant is associated with the following publications: (PMID: 8956040, 25563310, 19996202, 22462637, 27884173, 22799452, 26332594, 20034980, 25985138, 27527340, 19906784, 22438210, 27057652, 25078357, 27069690, 27439424, 20518900, 8730290, 9829911, 21972040) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 30, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Benign

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.96

dbscSNV1_RF

Benign

0.67

SpliceAI score (max)

0.040

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