rs373068386

Variant names:

• chr3-10142001-G-A
• rs373068386
• NM_000551.4:c.154G>A
• VHL p.Glu52Lys

Your query was ambiguous. Multiple possible variants found:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). BP6_Strong

The NM_000551.4(VHL):c.154G>A (p.Glu52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000676 (AC=107) in the gnomAD database across 1,583,178 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.00116. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E52*: Uncertain_significance (ClinVar VariationId 182982, 2 stars); p.E52= (synonymous): Likely_benign (ClinVar VariationId 1665243, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar ≥3 stars benign with significant pathogenic submissions — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s), conflicting pathogenic submissions present (B/LB: 8, P/LP: 2).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated classification 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	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.154G>A p.Glu52Lys	missense	Exon 1 of 3	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.154G>A p.Glu52Lys	missense	Exon 1 of 2	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 3

missense

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 3

missense

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 2

missense

Prot: NP_937799.1UniProt: P40337-2A0A0S2Z4K1

Ensembl Transcripts

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

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 3

missense

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 2

missense

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.200G>A

Exon rankExon 1 of 3

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000197	AC:30	Hom:1	AN:152242	Cov:33
GnomAD2 exomes	AF: 0.0000627	AC:12	Hom:	AN:191496	Cov:
GnomAD4 exome	AF: 0.0000538	AC:77	Hom:1	AN:1430820	Cov:32
GnomAD4 genome	AF: 0.000197	AC:30	Hom:0	AN:152358	Cov:33
TOPMed (Bravo)	AF: 0.000332	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000968	AC:7	Hom:0	AN:72282	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2340	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000241	AC:3	Hom:	AN:12440	Cov:
GenomeAsia100K	AF: 0.000577	AC:2	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.000700	AC:1	Hom:	AN:1504	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.000429	18	41944	0.000269	18	66888
SCHEMA(Schizophrenia)	0.00240	264	110016	0.00261	478	183304

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.8
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
FuncVEP CTI	Benign	0.0035
GPN-Star LLR	N/A	-1.5
GPN-Star score	N/A	1.5
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.69	T
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Benign	0.55	N
PhyloP100	Benign	0.42
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.70	T
PromoterAI	N/A	-0.046	Neutral
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.021	D
Sift4G	Benign	0.21	T
Varity_R	N/A	0.20
VESM-3B	Benign	-7.2

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs373068386;

hg19: chr3-10183685;

COSMIC: COSV56549582;

COSMIC: COSV56549582;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar