chr3-10142019-C-G

Position:

• chr3-10142019-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000551.4(VHL):​c.172C>G​(p.Arg58Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

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 4 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.172C>G	p.Arg58Gly	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.172C>G	p.Arg58Gly	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.172C>G	p.Arg58Gly	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.242C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.172C>G	p.Arg58Gly	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	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	0.090
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.021	.;D
Sift4G	Uncertain	0.050	T;D
Polyphen		0.32	B;B
Vest4		0.23
MutPred		0.57		Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);
MVP		0.98
MPC		0.67
ClinPred		0.76	D
GERP RS		3.7
Varity_R		0.62
gMVP		0.88

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: chr3-10183703;