3-10146625-T-G

Position:

• chr3-10146625-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000551.4(VHL):​c.452T>G​(p.Ile151Ser) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I151M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P: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]

VHL (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• 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 chr3-10146626-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-10146625-T-G is Pathogenic according to our data. Variant chr3-10146625-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 223215.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-10146625-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.452T>G	p.Ile151Ser	missense_variant	2/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3162T>G		intron_variant			NP_001341652.1
VHL	NM_198156.3	c.341-3162T>G		intron_variant			NP_937799.1
VHL	NR_176335.1	n.781T>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.452T>G	p.Ile151Ser	missense_variant	2/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Feb 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.98
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.84		Loss of sheet (P = 0.0025);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs869025655; hg19: chr3-10188309; COSMIC: COSV56545117;