rs755333116

chr3-10141861-C-Gchr3-10141861-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000551.4(VHL):c.14C>G(p.Ala5Gly) 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 benign outcome for this variant. 14/21 in silico tools predict a benign 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. A5S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 312 pathogenic changes around while only 40 benign (89%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.189991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.14C>G	p.Ala5Gly	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.14C>G	p.Ala5Gly	missense_variant	1/3
VHL	NM_198156.3	c.14C>G	p.Ala5Gly	missense_variant	1/2
VHL	NR_176335.1	n.84C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.14C>G	p.Ala5Gly	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	Benign	0.081
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.24
Sift4G	Benign	0.34	T;T
Polyphen		0.77	P;D
Vest4		0.17
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.97
MPC		0.66
ClinPred		0.63	D
GERP RS		2.9
Varity_R		0.30
gMVP		0.20

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: chr3-10183545;