chr3-10142080-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):​c.233A>C​(p.Asn78Thr) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N78S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

VHL
NM_000551.4 missense

Scores

14
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.72
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 Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain 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 chr3-10142080-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 93326.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 3-10142080-A-C is Pathogenic according to our data. Variant chr3-10142080-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 223168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VHLNM_000551.4 linkuse as main transcriptc.233A>C p.Asn78Thr missense_variant 1/3 ENST00000256474.3
VHLNM_001354723.2 linkuse as main transcriptc.233A>C p.Asn78Thr missense_variant 1/3
VHLNM_198156.3 linkuse as main transcriptc.233A>C p.Asn78Thr missense_variant 1/2
VHLNR_176335.1 linkuse as main transcriptn.303A>C non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.233A>C p.Asn78Thr missense_variant 1/31 NM_000551.4 P1P40337-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaFeb 26, 2016- -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeFeb 05, 2022This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 78 of the VHL protein (p.Asn78Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 8956040, 18446368; Invitae). ClinVar contains an entry for this variant (Variation ID: 223168). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant disrupts the p.Asn78 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 16, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;.
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;T
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Uncertain
2.6
M;M
MutationTaster
Benign
0.99
D;D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
.;D
Sift4G
Benign
0.074
T;D
Polyphen
1.0
D;D
Vest4
0.96
MutPred
0.98
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP
1.0
MPC
1.1
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5030804; hg19: chr3-10183764; COSMIC: COSV56559393; COSMIC: COSV56559393; API