rs5030814

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The ENST00000256474.3(VHL):​c.463+2T>A 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. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

VHL
ENST00000256474.3 splice_donor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.18
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 Likely_pathogenic. Variant got 6 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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkuse as main transcriptc.463+2T>A splice_donor_variant ENST00000256474.3 NP_000542.1
VHLNM_001354723.2 linkuse as main transcriptc.*18-3149T>A intron_variant NP_001341652.1
VHLNM_198156.3 linkuse as main transcriptc.341-3149T>A intron_variant NP_937799.1
VHLNR_176335.1 linkuse as main transcriptn.792+2T>A splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.463+2T>A splice_donor_variant 1 NM_000551.4 ENSP00000256474 P1P40337-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
D;D
GERP RS
4.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.96
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.56
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10188322; COSMIC: COSV56543181; API