3-10142120-C-G

Position:

• chr3-10142120-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000551.4(VHL):​c.273C>G​(p.Phe91Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F91V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67

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 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.273C>G	p.Phe91Leu	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.273C>G	p.Phe91Leu	missense_variant	1/3
VHL	NM_198156.3	c.273C>G	p.Phe91Leu	missense_variant	1/2
VHL	NR_176335.1	n.343C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.273C>G	p.Phe91Leu	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.88	D;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.015	.;D
Sift4G	Benign	0.080	T;D
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.80		Gain of disorder (P = 0.1198);Gain of disorder (P = 0.1198);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.94
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10183804;