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 region, 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_region, intron

Scores

2
Splicing: ADA: 0.9553
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

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]

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 HGVSp Effect Exon rank MANE Protein UniProt
VHLNM_000551.4 linkc.340+5G>C splice_region_variant, intron_variant Intron 1 of 2 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.340+5G>C splice_region_variant, intron_variant Intron 1 of 2 NP_001341652.1
VHLNM_198156.3 linkc.340+5G>C splice_region_variant, intron_variant Intron 1 of 1 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.410+5G>C splice_region_variant, intron_variant Intron 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.340+5G>C splice_region_variant, intron_variant Intron 1 of 2 1 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
AF:
0.00401
AC:
610
AN:
152178
Hom.:
15
Cov.:
33
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.:
71
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.:
32
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.:
16
Cov.:
33
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.:
1
Bravo
AF:
0.00371
Asia WGS
AF:
0.0270
AC:
95
AN:
3476

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 03, 2018
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 15, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 21, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

not provided Benign:6
Nov 04, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

May 09, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 05, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 16, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Von Hippel-Lindau syndrome Benign:5
Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 21, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 04, 2015
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 26, 2016
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Feb 24, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 30, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.24
CADD
Benign
16
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.

Other links and lift over

dbSNP: rs61758376; hg19: chr3-10183876; COSMIC: COSV104558389; COSMIC: COSV104558389; API