GeneBe

rs1182227189

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_022051.3(EGLN1):​c.122_124delACT​(p.Tyr41del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000193 in 1,555,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.48
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_022051.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EGLN1NM_022051.3 linkc.122_124delACT p.Tyr41del disruptive_inframe_deletion Exon 1 of 5 ENST00000366641.4 NP_071334.1 Q9GZT9-1R4SCQ0
EGLN1NM_001377260.1 linkc.122_124delACT p.Tyr41del disruptive_inframe_deletion Exon 1 of 4 NP_001364189.1
EGLN1NM_001377261.1 linkc.122_124delACT p.Tyr41del disruptive_inframe_deletion Exon 1 of 4 NP_001364190.1
EGLN1XM_024447734.2 linkc.122_124delACT p.Tyr41del disruptive_inframe_deletion Exon 1 of 3 XP_024303502.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EGLN1ENST00000366641.4 linkc.122_124delACT p.Tyr41del disruptive_inframe_deletion Exon 1 of 5 1 NM_022051.3 ENSP00000355601.3 Q9GZT9-1
ENSG00000287856ENST00000662216.1 linkc.30+40671_30+40673delACT intron_variant Intron 3 of 6 ENSP00000499467.1 A0A590UJK7
ENSG00000287856ENST00000653908.1 linkc.30+40671_30+40673delACT intron_variant Intron 2 of 4 ENSP00000499669.1 A0A590UK27
ENSG00000287856ENST00000653198.1 linkn.433+40705_433+40707delACT intron_variant Intron 4 of 7

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151798
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00000142
AC:
2
AN:
1403650
Hom.:
0
AF XY:
0.00000287
AC XY:
2
AN XY:
697030
show subpopulations
Gnomad4 AFR exome
AF:
0.0000331
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.15e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151798
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74160
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3 Uncertain:1
Apr 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.122_124del, results in the deletion of 1 amino acid(s) of the EGLN1 protein (p.Tyr41del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with erythrocytosis (PMID: 34946900). ClinVar contains an entry for this variant (Variation ID: 534225). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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.

Other links and lift over

dbSNP: rs1182227189; hg19: chr1-231557510; API