3-10145330-A-G

Variant names:

• chr3-10145330-A-G
• rs779812
• NM_000551.4:c.341-1184A>G

Variant summary

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

The NM_000551.4(VHL):​c.341-1184A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,240 control chromosomes in the GnomAD database, including 60,696 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 0.89 (60696 hom., cov: 33)
• Consequence: VHL NM_000551.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.341-1184A>G		intron_variant	Intron 1 of 2	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*17+2309A>G		intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.340+3143A>G		intron_variant	Intron 1 of 1		NP_937799.1
VHL	NR_176335.1	n.670-1184A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.341-1184A>G		intron_variant	Intron 1 of 2	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135697 AN: 152122 Hom.: 60660 Cov.: 33

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.902

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.883

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

GnomAD4 genome AF: 0.892 AC: 135783 AN: 152240 Hom.: 60696 Cov.: 33 AF XY: 0.893 AC XY: 66447 AN XY: 74412

African (AFR) AF: 0.936 AC: 38902 AN: 41558

American (AMR) AF: 0.870 AC: 13286 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3220 AN: 3470

East Asian (EAS) AF: 0.885 AC: 4589 AN: 5186

South Asian (SAS) AF: 0.790 AC: 3814 AN: 4826

European-Finnish (FIN) AF: 0.902 AC: 9555 AN: 10592

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59516 AN: 68024

Other (OTH) AF: 0.876 AC: 1851 AN: 2114

Alfa AF: 0.882 Hom.: 5206

Bravo AF: 0.894

Asia WGS AF: 0.824 AC: 2867 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.1
DANN	Benign	0.91
PhyloP100		0.26
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: rs779812; hg19: chr3-10187014;