Genetic Variant VHLL:p.Arg4Thr (chr1-156299179-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001004319.3(VHLL):c.11G>C(p.Arg4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

VHLL
NM_001004319.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.256

Variant links:

Genes affected

VHLL (HGNC:30666): (VHL like) Von Hippel-Lindau (VHL) tumor suppressor protein is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the alpha subunit of the hypoxia-inducible factor (HIF) transcription factor for proteasome-mediated degradation. Inactivation of VHL causes VHL disease and sporadic kidney cancer. This gene encodes a VHL homolog that lacks one of two key domains necessary for VHL function. This gene may contribute to the regulation of oxygen homeostasis and neovascularization during placenta development. This gene is intronless, and can also be interpreted as a retrotransposed pseudogene of the VHL locus located on chromosome 3. However, the protein is represented in this RefSeq due to evidence in PMID:14757845 that strongly suggests it is translated. The same publication also indicates that this protein binds HIF alpha but fails to recruit the E3 ubiquitin ligase complex, and it therefore functions as a dominant-negative VHL protein and a protector of HIF alpha. [provided by RefSeq, Jan 2010]

VHLL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.088308126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHLL	NM_001004319.3 link	c.11G>C	p.Arg4Thr	missense_variant	Exon 1 of 1	ENST00000339922.5	NP_001004319.1	Q6RSH7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHLL	ENST00000339922.5 link	c.11G>C	p.Arg4Thr	missense_variant	Exon 1 of 1	6	NM_001004319.3	ENSP00000464258.2		Q6RSH7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410958

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32200

American (AMR)

AF:

0.00

AC:

AN:

38578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22302

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39284

South Asian (SAS)

AF:

0.00

AC:

AN:

77466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086324

Other (OTH)

AF:

0.00

AC:

AN:

58152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 29, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.11G>C (p.R4T) alteration is located in exon 1 (coding exon 1) of the VHLL gene. This alteration results from a G to C substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

7.4

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.016

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.27

M_CAP

Benign

0.0062

MetaRNN

Benign

0.088

MutationAssessor

Benign

0.0

PhyloP100

-0.26

PrimateAI

Benign

0.44

Sift4G

Uncertain

0.034

Polyphen

0.59

Vest4

0.098

MVP

0.77

MPC

0.21

GERP RS

-0.65

PromoterAI

-0.0087

Neutral

(source)

Varity_R

0.15

gMVP

0.34

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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chr1-156299179-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over