Genetic Variant EGLN1:c.891+19292G>A (chr1-231401706-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022051.3(EGLN1):c.891+19292G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,984 control chromosomes in the GnomAD database, including 24,214 homozygotes. 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: 𝑓 0.54 ( 24214 hom., cov: 33)

Consequence

EGLN1
NM_022051.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.103

Publications

6 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: Ambry Genetics, Genomics England PanelApp, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
EGLN1	NM_022051.3	MANE Select	c.891+19292G>A	intron	N/A	NP_071334.1	R4SCQ0
EGLN1	NM_001377260.1		c.891+19292G>A	intron	N/A	NP_001364189.1
EGLN1	NM_001377261.1		c.891+19292G>A	intron	N/A	NP_001364190.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.891+19292G>A	intron	N/A	ENSP00000355601.3	Q9GZT9-1
ENSG00000287856	ENST00000662216.1		c.31-27607G>A	intron	N/A	ENSP00000499467.1	A0A590UJK7
EGLN1	ENST00000476717.2	TSL:1	n.168+18470G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.545

AC:

82795

AN:

151866

Hom.:

24208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.315

Gnomad AMI

AF:

0.679

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.549

Gnomad SAS

AF:

0.571

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.652

Gnomad OTH

AF:

0.564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.545

AC:

82823

AN:

151984

Hom.:

24214

Cov.:

AF XY:

0.550

AC XY:

40871

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.314

AC:

13030

AN:

41456

American (AMR)

AF:

0.542

AC:

8278

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

2169

AN:

3472

East Asian (EAS)

AF:

0.549

AC:

2814

AN:

5124

South Asian (SAS)

AF:

0.572

AC:

2758

AN:

4818

European-Finnish (FIN)

AF:

0.710

AC:

7499

AN:

10558

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.652

AC:

44281

AN:

67962

Other (OTH)

AF:

0.562

AC:

1187

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1796

3592

5389

7185

8981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.498

Hom.:

2294

Bravo

AF:

0.523

Asia WGS

AF:

0.557

AC:

1932

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

3.5

(source)

DANN

Benign

0.67

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over