chr3-10146639-A-G

Variant names:

• chr3-10146639-A-G
• rs1131690954
• NM_000551.4:c.463+3A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000551.4(VHL):​c.463+3A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 splice_region, intron
• Scores: Splicing: ADA: 0.9944
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 4.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-10146639-A-G is Pathogenic according to our data. Variant chr3-10146639-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428796.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}. Variant chr3-10146639-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.463+3A>G		splice_region_variant, intron_variant	Intron 2 of 2	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3148A>G		intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.341-3148A>G		intron_variant	Intron 1 of 1		NP_937799.1
VHL	NR_176335.1	n.792+3A>G		splice_region_variant, intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.463+3A>G		splice_region_variant, intron_variant	Intron 2 of 2	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Apr 12, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant of interest is located at a conserved intronic position with 3/5 in silico programs via Alamut predicting an effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in affected individuals via publications. However, no reputable databases and/or clinical laboratories cite the variant. Although, another variant at this position, c.463+3A>T has been reported in affected individuals via publications. Therefore, taking all lines of evidence into consideration, the variant of interest is classified as VUS-possibly pathogenic until additional information becomes available. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Von Hippel-Lindau syndrome Pathogenic:1

Mar 10, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22145147, 22438210]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 04, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.463+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 2 in the VHL gene. This intronic alteration (designated as IVS2+3A>G), was reported in an 18-year-old female with bilateral pheochromocytomas and a pancreatic neuroendocrine tumor. Her family history included CNS tumors, hemangioblastomas, and adrenal tumors (Boaz RJ et al. Indian J. Endocrinol. Metab. 2011 Oct;15 Suppl 4:S402-5; Ebenazer A et al. Fam. Cancer. 2013 Sep;12(3):519-24). It was confirmed to be de novo in a patient with a history of pheochromocytoma, pancreatic neuroendocrine tumor, and CNS hemangioblastomas (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Pheochromocytoma Uncertain:1

Jan 03, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported to be associated with VHL related disorder (ClinVar ID: VCV000428796).It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

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

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the VHL gene. It does not directly change the encoded amino acid sequence of the VHL protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with von Hippel-Lindau syndrome (PMID: 22145147, 22438210; Invitae). This variant is also known as IVS2+3A>G. ClinVar contains an entry for this variant (Variation ID: 428796). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 37
DS_DL_spliceai		0.76		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131690954; hg19: chr3-10188323;