Variant rs5030833 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PM5PP3_Strong

The NM_000551.4(VHL):c.407T>A(p.Phe136Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F136L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1

Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a region_of_interest Involved in binding to CCT complex (size 55) in uniprot entity VHL_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) in NM_000551.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-10146581-T-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.407T>A	p.Phe136Tyr	missense_variant	2/3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.*18-3207T>A		intron_variant			NP_001341652.1
VHL	NM_198156.3 link	c.341-3207T>A		intron_variant			NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.736T>A		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.407T>A	p.Phe136Tyr	missense_variant	2/3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.55

Sift4G

Benign

0.15

Polyphen

0.40

Vest4

0.64

MutPred

0.91

Gain of sheet (P = 0.0344);

MVP

0.95

MPC

0.69

ClinPred

0.77

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.90

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

Computational scores

Splicing

Publications

Other links and lift over