Genetic Variant EGLN1:p.Asp4Glu (chr1-231421877-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022051.3(EGLN1):c.12C>G(p.Asp4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,488,446 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D4G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 51 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.787

Publications

45 publications found

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 Gene-Disease associations (from GenCC):

erythrocytosis, familial, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant secondary polycythemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin, high altitude adaptation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

EGLN1 links:

ENSG00000287856 (HGNC:):

ENSG00000287856 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003653556).

BP6

Variant 1-231421877-G-C is Benign according to our data. Variant chr1-231421877-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00141 (214/151930) while in subpopulation EAS AF = 0.0319 (163/5110). AF 95% confidence interval is 0.0279. There are 12 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 214 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022051.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EGLN1	NM_022051.3	MANE Select	c.12C>G	p.Asp4Glu	missense	Exon 1 of 5	NP_071334.1
EGLN1	NM_001377260.1		c.12C>G	p.Asp4Glu	missense	Exon 1 of 4	NP_001364189.1
EGLN1	NM_001377261.1		c.12C>G	p.Asp4Glu	missense	Exon 1 of 4	NP_001364190.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.12C>G	p.Asp4Glu	missense	Exon 1 of 5	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1		c.30+40561C>G		intron	N/A	ENSP00000499467.1
ENSG00000287856	ENST00000653908.1		c.30+40561C>G		intron	N/A	ENSP00000499669.1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

151820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0318

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00256

AC:

287

AN:

112318

AF XY:

0.00223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00638

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0202

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000242

Gnomad OTH exome

AF:

0.00143

GnomAD4 exome

AF:

0.00147

AC:

1970

AN:

1336516

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

993

AN XY:

662306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27656

American (AMR)

AF:

0.00493

AC:

146

AN:

29638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23178

East Asian (EAS)

AF:

0.0451

AC:

1366

AN:

30264

South Asian (SAS)

AF:

0.00184

AC:

135

AN:

73374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33838

Middle Eastern (MID)

AF:

0.00103

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.000181

AC:

192

AN:

1059690

Other (OTH)

AF:

0.00231

AC:

127

AN:

55004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

110

219

329

438

548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00141

AC:

214

AN:

151930

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

120

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41512

American (AMR)

AF:

0.00138

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0319

AC:

163

AN:

5110

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

67904

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000624

Hom.:

Bravo

AF:

0.00181

ExAC

AF:

0.00197

AC:

217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jul 27, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided

Benign:1

Jun 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EGLN1-related disorder

Benign:1

Aug 03, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.0

PhyloP100

0.79

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.070

REVEL

Benign

0.26

Sift

Benign

0.31

Sift4G

Benign

0.086

Polyphen

0.010

Vest4

0.0070

MutPred

0.099

Gain of solvent accessibility (P = 0.0808)

MVP

0.47

MPC

1.6

ClinPred

0.023

GERP RS

3.5

PromoterAI

0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.15

gMVP

0.15

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over