rs373068386

Variant names:

• chr3-10142001-G-A
• rs373068386
• NM_000551.4:c.154G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10142001-G-A
• chr3-10142001-G-T
• chr3-10142001-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.154G>A (p.Glu52Lys) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0008611 (78/74388 from African/African American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) 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/CA020056/MONDO:0008667/078

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (1 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:7 B:8
• Conservation: PhyloP100: 0.417
• Publications: 21 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• 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 -8 ACMG points.

• BA1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.154G>A	p.Glu52Lys	missense	Exon 1 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.154G>A	p.Glu52Lys	missense	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.154G>A	p.Glu52Lys	missense	Exon 1 of 2	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.154G>A	p.Glu52Lys	missense	Exon 1 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.154G>A	p.Glu52Lys	missense	Exon 1 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.200G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152242 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000627 AC: 12 AN: 191496 AF XY: 0.0000571

Gnomad AFR exome AF: 0.000703

Gnomad AMR exome AF: 0.0000688

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000703

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000202

GnomAD4 exome AF: 0.0000538 AC: 77 AN: 1430820 Hom.: 1 Cov.: 32 AF XY: 0.0000621 AC XY: 44 AN XY: 709086

African (AFR) AF: 0.00149 AC: 49 AN: 32794

American (AMR) AF: 0.000100 AC: 4 AN: 40000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37922

South Asian (SAS) AF: 0.0000363 AC: 3 AN: 82560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49164

Middle Eastern (MID) AF: 0.000900 AC: 5 AN: 5558

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1098170

Other (OTH) AF: 0.000169 AC: 10 AN: 59180

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74516

African (AFR) AF: 0.000697 AC: 29 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000300 Hom.: 0

Bravo AF: 0.000332

ESP6500AA AF: 0.000715 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000930 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	3	Von Hippel-Lindau syndrome (7)
-	2	1	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
1	-	-	Enchondromatosis (1)
1	-	-	Hepatoblastoma (1)
-	-	1	not specified (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	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.42
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.021	D
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.68
MVP		0.93
MPC		0.55
ClinPred		0.012	T
GERP RS		0.65
PromoterAI		-0.046	Neutral
Varity_R		0.20
gMVP		0.74
Mutation Taster		=30/70	disease causing

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: rs373068386; hg19: chr3-10183685; COSMIC: COSV56549582; COSMIC: COSV56549582;