rs397516443

Positions:

• chr3-10146638-T-C
• chr3-10146638-T-G
• chr3-10146638-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000256474.3(VHL):​c.463+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL ENST00000256474.3 splice_donor
• Scores: Splicing: ADA: 0.9895
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 6.18

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.19003116 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 40, new splice context is: gtgGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10146638-T-C is Pathogenic according to our data. Variant chr3-10146638-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 569414.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.463+2T>C		splice_donor_variant		ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3149T>C		intron_variant			NP_001341652.1
VHL	NM_198156.3	c.341-3149T>C		intron_variant			NP_937799.1
VHL	NR_176335.1	n.792+2T>C		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.463+2T>C		splice_donor_variant		1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2021

Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This donor splice site variant lies upstream of exon 3 sequence encoding the elongin C binding domain of VHL, which is required for protein stability and tumor suppressive activity (PMID: 9447969, 10900011, 14987375). Variants that disrupt this domain have been determined to be pathogenic (PMID: 9452032, 9829912, 17350623, 19602254, 25371412). This suggests that this region is critical for VHL protein function, and that other variants that disrupt this region may also be pathogenic. This variant has been reported in an individual with a personal and family history of von Hippel-Lindau syndrome (PMID: 8707293). This variant is also known as 676+2C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 569414). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 2) of the VHL gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. -

not provided Other:1

not provided, no classification provided

in vitro

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 38
DS_DL_spliceai		0.96		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs5030814; hg19: chr3-10188322; COSMIC: COSV56545468;