rs869025633

chr3-10142182-A-Cchr3-10142182-A-Gchr3-10142182-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000551.4(VHL):c.335A>C(p.Tyr112Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y112C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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 10 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr3-10142181-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.335A>C	p.Tyr112Ser	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.335A>C	p.Tyr112Ser	missense_variant	1/3
VHL	NM_198156.3	c.335A>C	p.Tyr112Ser	missense_variant	1/2
VHL	NR_176335.1	n.405A>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.335A>C	p.Tyr112Ser	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2017

The p.Y112S variant (also known as c.335A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 335. The tyrosine at codon 112 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.98	D;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.93
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.87		Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10183866;