chr3-10141894-A-G

Variant names:

• chr3-10141894-A-G
• rs864622379
• NM_000551.4:c.47A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000256474.3(VHL):​c.47A>G​(p.Glu16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,472 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. 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. E16V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VHL ENST00000256474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.380
• Publications: 0 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22513542).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000256474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.47A>G	p.Glu16Gly	missense	Exon 1 of 3	NP_000542.1
	VHL	NM_001354723.2		c.47A>G	p.Glu16Gly	missense	Exon 1 of 3	NP_001341652.1
	VHL	NM_198156.3		c.47A>G	p.Glu16Gly	missense	Exon 1 of 2	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.47A>G	p.Glu16Gly	missense	Exon 1 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.47A>G	p.Glu16Gly	missense	Exon 1 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.93A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380472 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 678502

African (AFR) AF: 0.00 AC: 0 AN: 30808

American (AMR) AF: 0.00 AC: 0 AN: 34028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24390

East Asian (EAS) AF: 0.00 AC: 0 AN: 35292

South Asian (SAS) AF: 0.00 AC: 0 AN: 77482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069408

Other (OTH) AF: 0.00 AC: 0 AN: 56936

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.38
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.023	D
Polyphen		0.95	P
Vest4		0.13
MutPred		0.24		Gain of loop (P = 0.0166)
MVP		0.96
MPC		0.65
ClinPred		0.38	T
GERP RS		1.1
PromoterAI		0.11	Neutral
Varity_R		0.26
gMVP		0.50
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs864622379; hg19: chr3-10183578;