rs119476044

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_022051.3(EGLN1):​c.1112G>A​(p.Arg371His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

13
4
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a domain Fe2OG dioxygenase (size 101) in uniprot entity EGLN1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_022051.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
PP5
Variant 1-231370598-C-T is Pathogenic according to our data. Variant chr1-231370598-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4356.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-231370598-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EGLN1NM_022051.3 linkuse as main transcriptc.1112G>A p.Arg371His missense_variant 3/5 ENST00000366641.4 NP_071334.1 Q9GZT9-1R4SCQ0
EGLN1NM_001377260.1 linkuse as main transcriptc.1112G>A p.Arg371His missense_variant 3/4 NP_001364189.1
EGLN1NM_001377261.1 linkuse as main transcriptc.1012-2962G>A intron_variant NP_001364190.1
EGLN1XM_024447734.2 linkuse as main transcriptc.1012-2962G>A intron_variant XP_024303502.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EGLN1ENST00000366641.4 linkuse as main transcriptc.1112G>A p.Arg371His missense_variant 3/51 NM_022051.3 ENSP00000355601.3 Q9GZT9-1
ENSG00000287856ENST00000662216.1 linkuse as main transcriptc.251G>A p.Arg84His missense_variant 5/7 ENSP00000499467.1 A0A590UJK7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461768
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 15, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.82
D
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.050
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
-0.060
T
MutationAssessor
Uncertain
2.8
M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.8
D
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.88
MutPred
0.88
Loss of solvent accessibility (P = 0.0128);
MVP
0.85
MPC
2.6
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.82
gMVP
0.96

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: rs119476044; hg19: chr1-231506344; API