3-10146639-A-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 donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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_donor_region, intron
• Scores: Splicing: ADA: 0.9944
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• 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, Pathogenic=1, Uncertain_significance=2}. Variant chr3-10146639-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.463+3A>G		splice_donor_region_variant, intron_variant		ENST00000256474.3
VHL	NM_001354723.2	c.*18-3148A>G		intron_variant
VHL	NM_198156.3	c.341-3148A>G		intron_variant
VHL	NR_176335.1	n.792+3A>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.463+3A>G		splice_donor_region_variant, intron_variant		1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2016	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Von Hippel-Lindau syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 10, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2019

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

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

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. -

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;