rs1064793290

Variant names:

• chr3-10141936-G-A
• rs1064793290
• NM_000551.4:c.89G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10141936-G-A
• chr3-10141936-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2_Supporting BS1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16617781/MONDO:0008667/078

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:6 B:3
• Conservation: PhyloP100: -1.79
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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.89G>A	p.Gly30Glu	missense	Exon 1 of 3	NP_000542.1
	VHL	NM_001354723.2		c.89G>A	p.Gly30Glu	missense	Exon 1 of 3	NP_001341652.1
	VHL	NM_198156.3		c.89G>A	p.Gly30Glu	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.89G>A	p.Gly30Glu	missense	Exon 1 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.89G>A	p.Gly30Glu	missense	Exon 1 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.135G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000345 AC: 5 AN: 144804 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 22 AN: 1388210 Hom.: 0 Cov.: 32 AF XY: 0.00000878 AC XY: 6 AN XY: 683154

African (AFR) AF: 0.0000642 AC: 2 AN: 31150

American (AMR) AF: 0.000200 AC: 7 AN: 34922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24788

East Asian (EAS) AF: 0.00 AC: 0 AN: 35550

South Asian (SAS) AF: 0.00 AC: 0 AN: 78262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4424

European-Non Finnish (NFE) AF: 0.0000112 AC: 12 AN: 1073666

Other (OTH) AF: 0.0000174 AC: 1 AN: 57392

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	1	Von Hippel-Lindau syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	VHL-related disorder (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.24
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.029	D
Polyphen		0.0030	B
Vest4		0.23
MutPred		0.19		Gain of solvent accessibility (P = 0.0456)
MVP		0.87
MPC		0.43
ClinPred		0.031	T
GERP RS		-3.1
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.077
gMVP		0.69
Mutation Taster		=88/12	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: rs1064793290; hg19: chr3-10183620;