rs561874453

chr3-10149877-A-Cchr3-10149877-A-Gchr3-10149877-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000551.4(VHL):c.554A>C(p.Tyr185Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y185C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.55

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 7 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.554A>C	p.Tyr185Ser	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3	c.431A>C	p.Tyr144Ser	missense_variant	2/2
VHL	NM_001354723.2	c.*108A>C		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.883A>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.554A>C	p.Tyr185Ser	missense_variant	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.041	D;D
Polyphen		1.0	D;P
Vest4		0.60
MutPred		0.68		Gain of disorder (P = 0.0032);.;
MVP		1.0
MPC		1.3
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.74

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: rs561874453; hg19: chr3-10191561;