Genetic Variant EGLN1:p.Gly135Gly (chr1-231421484-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_022051.3(EGLN1):c.405C>G(p.Gly135Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000828 in 1,207,432 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. Synonymous variant affecting the same amino acid position (i.e. G135G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00500

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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP7

Synonymous conserved (PhyloP=0.005 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
EGLN1	NM_022051.3 link	c.405C>G	p.Gly135Gly	synonymous_variant	Exon 1 of 5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1 link	c.405C>G	p.Gly135Gly	synonymous_variant	Exon 1 of 4		NP_001364189.1
EGLN1	NM_001377261.1 link	c.405C>G	p.Gly135Gly	synonymous_variant	Exon 1 of 4		NP_001364190.1
EGLN1	XM_024447734.2 link	c.405C>G	p.Gly135Gly	synonymous_variant	Exon 1 of 3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4 link	c.405C>G	p.Gly135Gly	synonymous_variant	Exon 1 of 5	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1 link	c.30+40954C>G		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.28e-7

AC:

AN:

1207432

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

582276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23466

American (AMR)

AF:

0.00

AC:

AN:

10720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16150

East Asian (EAS)

AF:

0.00

AC:

AN:

28354

South Asian (SAS)

AF:

0.00

AC:

AN:

44004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4330

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

990010

Other (OTH)

AF:

0.00

AC:

AN:

49166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.2

(source)

DANN

Benign

0.56

PhyloP100

0.0050

PromoterAI

-0.13

Neutral

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over