Variant 14-33950560-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022073.4(EGLN3):c.193C>T(p.Arg65Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EGLN3
NM_022073.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.76

Variant links:

Genes affected

EGLN3 (HGNC:14661): (egl-9 family hypoxia inducible factor 3) Enables peptidyl-proline 4-dioxygenase activity. Involved in several processes, including activation of cysteine-type endopeptidase activity involved in apoptotic process; peptidyl-proline hydroxylation to 4-hydroxy-L-proline; and response to hypoxia. Located in cytosol and nucleus. Implicated in renal cell carcinoma. Biomarker of clear cell renal cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

EGLN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13810092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN3	NM_022073.4 linkuse as main transcript	c.193C>T	p.Arg65Cys	missense_variant	1/5	ENST00000250457.9	NP_071356.1	Q9H6Z9
EGLN3	NM_001308103.2 linkuse as main transcript	c.75+118C>T		intron_variant			NP_001295032.1	Q9H6Z9Q3T1B0F8W1G2B3KVT0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGLN3	ENST00000250457.9 linkuse as main transcript	c.193C>T	p.Arg65Cys	missense_variant	1/5	1	NM_022073.4	ENSP00000250457.4	Q9H6Z9
EGLN3	ENST00000553215.5 linkuse as main transcript	c.75+118C>T		intron_variant		1		ENSP00000447470.1	F8W1G2
EGLN3	ENST00000547327.2 linkuse as main transcript	c.193C>T	p.Arg65Cys	missense_variant	1/1	6		ENSP00000446572.2	F8VR39
EGLN3	ENST00000487915.6 linkuse as main transcript	c.4-19345C>T		intron_variant		5		ENSP00000451316.1	G3V3M1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459626

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.193C>T (p.R65C) alteration is located in exon 1 (coding exon 1) of the EGLN3 gene. This alteration results from a C to T substitution at nucleotide position 193, causing the arginine (R) at amino acid position 65 to be replaced by a cysteine (C). 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

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.090

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.017

B;B

Vest4

0.17

MutPred

0.49

Gain of catalytic residue at P64 (P = 0.0069);Gain of catalytic residue at P64 (P = 0.0069);

MVP

0.40

MPC

1.4

ClinPred

0.81

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.59

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over