3-10150259-G-A

Variant names:

• chr3-10150259-G-A
• rs1642742
• NM_000551.4:c.*294G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000551.4(VHL):​c.*294G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 1,306,604 control chromosomes in the GnomAD database, including 288,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28081 hom., cov: 31)
  • Exomes 𝑓: 0.67 (260708 hom.)
• Consequence: VHL NM_000551.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.519
• Publications: 52 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

ENSG00000287086 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-10150259-G-A is Benign according to our data. Variant chr3-10150259-G-A is described in ClinVar as Benign. ClinVar VariationId is 342407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.*294G>A		3_prime_UTR	Exon 3 of 3	NP_000542.1
	VHL	NM_001354723.2		c.*490G>A		3_prime_UTR	Exon 3 of 3	NP_001341652.1
	VHL	NM_198156.3		c.*294G>A		3_prime_UTR	Exon 2 of 2	NP_937799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.*294G>A		3_prime_UTR	Exon 3 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.*294G>A		3_prime_UTR	Exon 2 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.1816G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88059 AN: 151868 Hom.: 28070 Cov.: 31

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.612

GnomAD4 exome AF: 0.668 AC: 770990 AN: 1154618 Hom.: 260708 Cov.: 45 AF XY: 0.665 AC XY: 368627 AN XY: 554038

African (AFR) AF: 0.263 AC: 6850 AN: 26008

American (AMR) AF: 0.654 AC: 10245 AN: 15662

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 11572 AN: 15794

East Asian (EAS) AF: 0.755 AC: 19108 AN: 25300

South Asian (SAS) AF: 0.549 AC: 32514 AN: 59248

European-Finnish (FIN) AF: 0.742 AC: 9880 AN: 13310

Middle Eastern (MID) AF: 0.617 AC: 1833 AN: 2970

European-Non Finnish (NFE) AF: 0.683 AC: 648770 AN: 950328

Other (OTH) AF: 0.657 AC: 30218 AN: 45998

GnomAD4 genome AF: 0.580 AC: 88099 AN: 151986 Hom.: 28081 Cov.: 31 AF XY: 0.587 AC XY: 43592 AN XY: 74304

African (AFR) AF: 0.289 AC: 11978 AN: 41450

American (AMR) AF: 0.656 AC: 10010 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2570 AN: 3466

East Asian (EAS) AF: 0.788 AC: 4069 AN: 5164

South Asian (SAS) AF: 0.556 AC: 2687 AN: 4830

European-Finnish (FIN) AF: 0.760 AC: 8019 AN: 10556

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46746 AN: 67948

Other (OTH) AF: 0.605 AC: 1276 AN: 2110

Alfa AF: 0.654 Hom.: 136934

Bravo AF: 0.560

Asia WGS AF: 0.652 AC: 2269 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Von Hippel-Lindau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.28
PhyloP100		0.52
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: rs1642742; hg19: chr3-10191943;