3-10141887-G-C

Variant names:

• chr3-10141887-G-C
• rs1060503559
• NM_000551.4:c.40G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000551.4(VHL):​c.40G>C​(p.Gly14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,380,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. G14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0950
• Publications: 1 publications found

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]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30373877).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.40G>C	p.Gly14Arg	missense	Exon 1 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.40G>C	p.Gly14Arg	missense	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.40G>C	p.Gly14Arg	missense	Exon 1 of 2	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.40G>C	p.Gly14Arg	missense	Exon 1 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.40G>C	p.Gly14Arg	missense	Exon 1 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.86G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000710 AC: 1 AN: 140840 AF XY: 0.0000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 15 AN: 1380760 Hom.: 0 Cov.: 32 AF XY: 0.00000737 AC XY: 5 AN XY: 678670

African (AFR) AF: 0.00 AC: 0 AN: 30830

American (AMR) AF: 0.00 AC: 0 AN: 33998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24422

East Asian (EAS) AF: 0.00 AC: 0 AN: 35300

South Asian (SAS) AF: 0.00 AC: 0 AN: 77542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4036

European-Non Finnish (NFE) AF: 0.0000131 AC: 14 AN: 1069582

Other (OTH) AF: 0.0000176 AC: 1 AN: 56946

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.095
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.31		Gain of helix (P = 0.0128)
MVP		0.93
MPC		1.1
ClinPred		0.51	D
GERP RS		2.4
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.068
gMVP		0.43
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1060503559; hg19: chr3-10183571;