rs753303580
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_022051.3(EGLN1):āc.833A>Gā(p.Asp278Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D278N) has been classified as Likely benign.
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000089 ( 0 hom. )
Consequence
EGLN1
NM_022051.3 missense
NM_022051.3 missense
Scores
1
15
3
Clinical Significance
Conservation
PhyloP100: 5.03
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_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EGLN1 | NM_022051.3 | c.833A>G | p.Asp278Gly | missense_variant | 1/5 | ENST00000366641.4 | NP_071334.1 | |
EGLN1 | NM_001377260.1 | c.833A>G | p.Asp278Gly | missense_variant | 1/4 | NP_001364189.1 | ||
EGLN1 | NM_001377261.1 | c.833A>G | p.Asp278Gly | missense_variant | 1/4 | NP_001364190.1 | ||
EGLN1 | XM_024447734.2 | c.833A>G | p.Asp278Gly | missense_variant | 1/3 | XP_024303502.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EGLN1 | ENST00000366641.4 | c.833A>G | p.Asp278Gly | missense_variant | 1/5 | 1 | NM_022051.3 | ENSP00000355601.3 | ||
ENSG00000287856 | ENST00000662216.1 | c.30+41382A>G | intron_variant | ENSP00000499467.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151996Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
151996
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD3 exomes
AF:
AC:
2
AN:
251476
Hom.:
AF XY:
AC XY:
1
AN XY:
135920
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727248
GnomAD4 exome
AF:
AC:
13
AN:
1461890
Hom.:
Cov.:
31
AF XY:
AC XY:
3
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151996Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74246
GnomAD4 genome
AF:
AC:
1
AN:
151996
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74246
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2023 | The p.D278G variant (also known as c.833A>G), located in coding exon 1 of the EGLN1 gene, results from an A to G substitution at nucleotide position 833. The aspartic acid at codon 278 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Erythrocytosis, familial, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 407208). This variant has not been reported in the literature in individuals affected with EGLN1-related conditions. This variant is present in population databases (rs753303580, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 278 of the EGLN1 protein (p.Asp278Gly). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of MoRF binding (P = 0.0486);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at