3-10146508-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000551.4(VHL):​c.341-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,434 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

VHL
NM_000551.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00001613
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.267
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 3-10146508-C-T is Benign according to our data. Variant chr3-10146508-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 371898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000184 (28/152166) while in subpopulation AFR AF= 0.000602 (25/41536). AF 95% confidence interval is 0.000418. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VHLNM_000551.4 linkc.341-6C>T splice_region_variant, intron_variant Intron 1 of 2 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.*18-3279C>T intron_variant Intron 2 of 2 NP_001341652.1
VHLNM_198156.3 linkc.341-3279C>T intron_variant Intron 1 of 1 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.670-6C>T splice_region_variant, intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.341-6C>T splice_region_variant, intron_variant Intron 1 of 2 1 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152048
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000604
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000596
AC:
15
AN:
251490
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.000738
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461268
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
726914
show subpopulations
Gnomad4 AFR exome
AF:
0.000777
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.000602
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000253
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Benign:3
Jul 29, 2016
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 11, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Nov 20, 2023
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2
Jun 08, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 25, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: VHL c.341-6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-05 in 282842 control chromosomes (gnomAD), predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 38 fold of the estimated maximal expected allele frequency for a pathogenic variant in VHL causing Von Hippel-Lindau Syndrome (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.341-6C>T has been reported in the literature in an individual affected with intracranial aneurysms (Klingler_2013) and an individual with Pheochromocytomas (Ben Aim_2019). These reports do not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30877234, 23434161). Five ClinVar submitters have assessed the variant since 2014: four classified the variant as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

VHL-related disorder Benign:1
Jul 06, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Apr 19, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30877234, 22517557, 27994516, 23434161) -

Hereditary cancer-predisposing syndrome Benign:1
Dec 04, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
4.5
DANN
Benign
0.44
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000016
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.14
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: rs191201783; hg19: chr3-10188192; COSMIC: COSV56547570; API