Variant 3-10142131-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000551.4(VHL):c.284C>G(p.Pro95Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P95L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.45

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]

VHL links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_000551.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 3-10142131-C-G is Pathogenic according to our data. Variant chr3-10142131-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1326284.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VHL	NM_000551.4 linkuse as main transcript	c.284C>G	p.Pro95Arg	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2 linkuse as main transcript	c.284C>G	p.Pro95Arg	missense_variant	1/3
VHL	NM_198156.3 linkuse as main transcript	c.284C>G	p.Pro95Arg	missense_variant	1/2
VHL	NR_176335.1 linkuse as main transcript	n.354C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.284C>G	p.Pro95Arg	missense_variant	1/3	1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University

Oct 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.012

.;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

D;D

Vest4

0.50

MutPred

0.82

Loss of glycosylation at P99 (P = 0.0223);Loss of glycosylation at P99 (P = 0.0223);

MVP

1.0

MPC

0.96

ClinPred

0.99

GERP RS

4.3

Varity_R

0.92

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over