rs779808

Variant names:

• chr3-10143337-C-T
• rs779808
• NM_000551.4:c.340+1150C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000551.4(VHL):​c.340+1150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,910 control chromosomes in the GnomAD database, including 27,799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (27799 hom., cov: 32)
• Consequence: VHL NM_000551.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.340+1150C>T		intron	N/A	NP_000542.1
	VHL	NM_001354723.2		c.*17+316C>T		intron	N/A	NP_001341652.1
	VHL	NM_198156.3		c.340+1150C>T		intron	N/A	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.340+1150C>T		intron	N/A	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.340+1150C>T		intron	N/A	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.1220+316C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86477 AN: 151792 Hom.: 27785 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.740

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.606

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.570 AC: 86519 AN: 151910 Hom.: 27799 Cov.: 32 AF XY: 0.577 AC XY: 42855 AN XY: 74248

African (AFR) AF: 0.245 AC: 10148 AN: 41368

American (AMR) AF: 0.653 AC: 9963 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 2569 AN: 3470

East Asian (EAS) AF: 0.789 AC: 4078 AN: 5168

South Asian (SAS) AF: 0.559 AC: 2699 AN: 4828

European-Finnish (FIN) AF: 0.760 AC: 8027 AN: 10560

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.692 AC: 47025 AN: 67952

Other (OTH) AF: 0.599 AC: 1265 AN: 2112

Alfa AF: 0.610 Hom.: 3968

Bravo AF: 0.548

Asia WGS AF: 0.654 AC: 2274 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.8
DANN	Benign	0.96
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: rs779808; hg19: chr3-10185021;