1-231421331-C-G

Position:

chr1-231421331-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_022051.3(EGLN1):c.558G>C(p.Lys186Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,611,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.07

Variant links:

Genes affected

EGLN1 (HGNC:1232): (egl-9 family hypoxia inducible factor 1) The protein encoded by this gene catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. This protein functions as a cellular oxygen sensor, and under normal oxygen concentration, modification by prolyl hydroxylation is a key regulatory event that targets HIF subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylation complex. Mutations in this gene are associated with erythrocytosis familial type 3 (ECYT3). [provided by RefSeq, Nov 2009]

EGLN1 links:

ENSG00000287856 (HGNC:):

ENSG00000287856 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07357824).

BP6

Variant 1-231421331-C-G is Benign according to our data. Variant chr1-231421331-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465825.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN1	NM_022051.3 linkuse as main transcript	c.558G>C	p.Lys186Asn	missense_variant	1/5	ENST00000366641.4	NP_071334.1	Q9GZT9-1R4SCQ0
EGLN1	NM_001377260.1 linkuse as main transcript	c.558G>C	p.Lys186Asn	missense_variant	1/4		NP_001364189.1
EGLN1	NM_001377261.1 linkuse as main transcript	c.558G>C	p.Lys186Asn	missense_variant	1/4		NP_001364190.1
EGLN1	XM_024447734.2 linkuse as main transcript	c.558G>C	p.Lys186Asn	missense_variant	1/3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGLN1	ENST00000366641.4 linkuse as main transcript	c.558G>C	p.Lys186Asn	missense_variant	1/5	1	NM_022051.3	ENSP00000355601.3	Q9GZT9-1
ENSG00000287856	ENST00000662216.1 linkuse as main transcript	c.30+41107G>C		intron_variant				ENSP00000499467.1	A0A590UJK7
ENSG00000287856	ENST00000653908.1 linkuse as main transcript	c.30+41107G>C		intron_variant				ENSP00000499669.1	A0A590UK27
ENSG00000287856	ENST00000653198.1 linkuse as main transcript	n.433+41141G>C		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000195

AC:

AN:

240640

Hom.:

AF XY:

0.000144

AC XY:

AN XY:

131972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000473

Gnomad NFE exome

AF:

0.000402

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000470

AC:

686

AN:

1459488

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

318

AN XY:

725940

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.000607

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000177

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000447

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000141

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 186 of the EGLN1 protein (p.Lys186Asn). This variant is present in population databases (rs201365992, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EGLN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 465825). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.72

M_CAP

Benign

0.039

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

REVEL

Benign

0.040

Sift

Benign

0.28

Sift4G

Benign

0.34

Polyphen

0.43

Vest4

0.051

MutPred

0.33

Loss of ubiquitination at K186 (P = 0.0087);

MVP

0.51

MPC

1.6

ClinPred

0.073

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.57

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over