1-231421613-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_022051.3(EGLN1):c.276G>C(p.Glu92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,349,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E92A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.502

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10412976).

BP6

Variant 1-231421613-C-G is Benign according to our data. Variant chr1-231421613-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435034.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000105 (16/151778) while in subpopulation AFR AF = 0.000387 (16/41382). AF 95% confidence interval is 0.000242. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3 link	c.276G>C	p.Glu92Asp	missense_variant	Exon 1 of 5	ENST00000366641.4	NP_071334.1	Q9GZT9-1R4SCQ0
EGLN1	NM_001377260.1 link	c.276G>C	p.Glu92Asp	missense_variant	Exon 1 of 4		NP_001364189.1
EGLN1	NM_001377261.1 link	c.276G>C	p.Glu92Asp	missense_variant	Exon 1 of 4		NP_001364190.1
EGLN1	XM_024447734.2 link	c.276G>C	p.Glu92Asp	missense_variant	Exon 1 of 3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EGLN1	ENST00000366641.4 link	c.276G>C	p.Glu92Asp	missense_variant	Exon 1 of 5	1	NM_022051.3	ENSP00000355601.3	Q9GZT9-1
ENSG00000287856	ENST00000662216.1 link	c.30+40825G>C		intron_variant	Intron 3 of 6			ENSP00000499467.1	A0A590UJK7
ENSG00000287856	ENST00000653908.1 link	c.30+40825G>C		intron_variant	Intron 2 of 4			ENSP00000499669.1	A0A590UK27
ENSG00000287856	ENST00000653198.1 link	n.433+40859G>C		intron_variant	Intron 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151778

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000835

AC:

AN:

1198206

Hom.:

Cov.:

AF XY:

0.0000120

AC XY:

AN XY:

584020

show subpopulations

African (AFR)

AF:

0.000423

AC:

AN:

23650

American (AMR)

AF:

0.00

AC:

AN:

9964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16294

East Asian (EAS)

AF:

0.00

AC:

AN:

27188

South Asian (SAS)

AF:

0.00

AC:

AN:

46866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3352

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

993054

Other (OTH)

AF:

0.00

AC:

AN:

48932

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

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:

0.000105

AC:

AN:

151778

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.000387

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67896

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.000121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3

Uncertain:1

Mar 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 92 of the EGLN1 protein (p.Glu92Asp). This variant is present in population databases (no rsID available, gnomAD 0.03%). 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: 435034). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 specified

Benign:1

Dec 30, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.6

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.24

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.47

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.55

PhyloP100

-0.50

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.36

REVEL

Benign

0.17

Sift

Benign

0.38

Sift4G

Benign

0.36

Polyphen

0.21

Vest4

0.057

MutPred

0.094

Gain of loop (P = 0.0502);

MVP

0.55

MPC

1.3

ClinPred

0.070

GERP RS

-1.6

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.030

gMVP

0.23

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over