rs104893824

Positions:

• chr3-10142181-T-A
• chr3-10142181-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.334T>A​(p.Tyr112Asn) 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 0.991
• PP5: Variant 3-10142181-T-A is Pathogenic according to our data. Variant chr3-10142181-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.334T>A	p.Tyr112Asn	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.334T>A	p.Tyr112Asn	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.334T>A	p.Tyr112Asn	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.404T>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.334T>A	p.Tyr112Asn	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 19, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2016	Variant summary: c.334T>A affects a conserved nucleotide, resulting in amino acid change from Tyr to Asn. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 91896 control chromosomes. This variant has been reported in multiple VHL pts with clear co-segregation of the variant with disease in the families (Bradley_1999 and Yoshida_2000). Functional studies showed that cell lines with variant have increased level of HIF2alpha (the critical oncogenic pVHL substrate in renal carcinogenesis) and its targets, the Y112N-producing cells formed large tumors (Li_2007), and the cell lines with variant showed disorganized fibroblast-like morphology and higher level of alpha5 integrin (Bangiyeva_2009). OMIM (also via ClinVar) lists this variant with classification of pathogenic. Taken together, this variant was classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0070	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.94		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.94
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

Other links and lift over

dbSNP: rs104893824; hg19: chr3-10183865;