rs863224839

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4BP6

The NM_000551.4(VHL):c.123_137delAGAGTCCGGCCCGGA(p.Glu42_Glu46del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,546,858 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E41E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

VHL
NM_000551.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.790

Publications

2 publications found

Variant links:

COSMIC-nc: COSV56543893

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

VHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000551.4.

BP6

Variant 3-10141955-GGAGTCCGGCCCGGAA-G is Benign according to our data. Variant chr3-10141955-GGAGTCCGGCCCGGAA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216870.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.123_137delAGAGTCCGGCCCGGA	p.Glu42_Glu46del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_001354723.2 link	c.123_137delAGAGTCCGGCCCGGA	p.Glu42_Glu46del	disruptive_inframe_deletion	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3 link	c.123_137delAGAGTCCGGCCCGGA	p.Glu42_Glu46del	disruptive_inframe_deletion	Exon 1 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NR_176335.1 link	n.193_207delAGAGTCCGGCCCGGA		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.123_137delAGAGTCCGGCCCGGA	p.Glu42_Glu46del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000733

AC:

AN:

150148

AF XY:

0.0000867

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000767

AC:

107

AN:

1394526

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

687030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31380

American (AMR)

AF:

0.00

AC:

AN:

35382

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25040

East Asian (EAS)

AF:

0.00

AC:

AN:

35748

South Asian (SAS)

AF:

0.000227

AC:

AN:

79164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48170

Middle Eastern (MID)

AF:

0.000210

AC:

AN:

4772

European-Non Finnish (NFE)

AF:

0.0000771

AC:

AN:

1077154

Other (OTH)

AF:

0.0000693

AC:

AN:

57716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Uncertain:1Benign:1

Aug 07, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Uncertain:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.123_137del, results in the deletion of 5 amino acid(s) of the VHL protein (p.Ser43_Glu47del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758049121, gnomAD 0.03%). This variant has been observed in individual(s) with von Hippel-Lindau (VHL) disease (PMID: 15300849, 37937776). ClinVar contains an entry for this variant (Variation ID: 216870). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.123_137del15 variant (also known as p.E43_P47del) is located in coding exon 1 of the VHL gene. This variant results from an in-frame deletion of 15 nucleotides (AGAGTCCGGCCCGGA) at positions 123 to 137. This results in the in-frame deletion of 5 amino acids (SGPEE) at codons 43 through 47. This alteration has been previously identified in an individual from the French VHL Registry (Gallou C, et al. Hum. Mutat. 2004 Sep;24(3):215-24). However, there is an alternate in-frame methionine 54 amino acids from the primary initiation site in VHL which is reported to result in a biologically active isoform known as VHL19 (Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6. Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22). The amino acids impacted by the c.123_137del15 alteration are located 5' of this alternative initiation codon and as such their significance is unclear. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided

Benign:1

Mar 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15300849) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.79

Mutation Taster

=69/131

disease causing (long InDel)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over