rs1553619461

Positions:

• chr3-10142160-A-C
• chr3-10142160-A-G
• chr3-10142160-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_000551.4(VHL):​c.313A>C​(p.Thr105Pro) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.99

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 Likely_pathogenic. Variant got 7 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• PP5: Variant 3-10142160-A-C is Pathogenic according to our data. Variant chr3-10142160-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 496055.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.313A>C	p.Thr105Pro	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.313A>C	p.Thr105Pro	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.313A>C	p.Thr105Pro	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.383A>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.313A>C	p.Thr105Pro	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Swedish Neurofibromatosis Center, Swedish Medical Center	Dec 03, 2020	PM1 Located in a mutational hot spot. PM2 Absent from controls. PP2 Missense variant in a gene that has a low rate. PP3 Multiple lines of computational evidence. PP4 Patient's phenotype is highly specific for a disease with a single genetic etiology. PP5 Reputable source recently reports variant as pathogenic. ClinVar classifies this variant as Pathogenic VCV000496055. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.036	.;D
Sift4G	Uncertain	0.053	T;D
Polyphen		0.93	P;P
Vest4		0.71
MutPred		0.70		Loss of glycosylation at P103 (P = 0.0211);Loss of glycosylation at P103 (P = 0.0211);
MVP		1.0
MPC		1.1
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.93

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

Other links and lift over

dbSNP: rs1553619461; hg19: chr3-10183844; COSMIC: COSV56570131; COSMIC: COSV56570131;