chr3-10149786-G-T

Variant names:

• chr3-10149786-G-T
• rs5030817
• NM_000551.4:c.464-1G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000551.4(VHL):​c.464-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.78

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]

ENSG00000287086 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10149786-G-T is Pathogenic according to our data. Variant chr3-10149786-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 223221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.464-1G>T		splice_acceptor_variant, intron_variant	Intron 2 of 2	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-1G>T		splice_acceptor_variant, intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.341-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 1		NP_937799.1
VHL	NR_176335.1	n.793-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.464-1G>T		splice_acceptor_variant, intron_variant	Intron 2 of 2	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 223221). This variant is also known as c.677-1G>T. Disruption of this splice site has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7987306, 8641976, 8707293, 17024664, 27439424, 33004005). It has also been observed to segregate with disease in related individuals. This sequence change affects an acceptor splice site in intron 2 of the VHL gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 08, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 3 of the VHL gene. This variant was reported in individuals with features consistent with von Hippel-Lindau syndrome (Ambry internal data; Crossey PA et al. Hum Mol Genet 1994 Aug;3(8):1303-8; Lee JS. et al. BMC Med Genet 2016 Jul;17(1):48; Kong W et al. Front Oncol 2021 Dec;11:737547). In addition, another alteration at this nucleotide position (c.464-1G>A) have also been reported in VHL families and is considered pathogenic (Ambry internal data, Glavac D et al. Hum Genet, 1996 Sep;98:271-80). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

not provided Other:1

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MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.91	D
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.69		Position offset: 16
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5030817; hg19: chr3-10191470; COSMIC: COSV56542304;