chr1-231421644-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_022051.3(EGLN1):​c.245C>T​(p.Ala82Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 1,302,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A82A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

1
2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.171
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 Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10816017).
BP6
Variant 1-231421644-G-A is Benign according to our data. Variant chr1-231421644-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534224.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EGLN1NM_022051.3 linkc.245C>T p.Ala82Val missense_variant Exon 1 of 5 ENST00000366641.4 NP_071334.1 Q9GZT9-1R4SCQ0
EGLN1NM_001377260.1 linkc.245C>T p.Ala82Val missense_variant Exon 1 of 4 NP_001364189.1
EGLN1NM_001377261.1 linkc.245C>T p.Ala82Val missense_variant Exon 1 of 4 NP_001364190.1
EGLN1XM_024447734.2 linkc.245C>T p.Ala82Val missense_variant Exon 1 of 3 XP_024303502.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EGLN1ENST00000366641.4 linkc.245C>T p.Ala82Val missense_variant Exon 1 of 5 1 NM_022051.3 ENSP00000355601.3 Q9GZT9-1
ENSG00000287856ENST00000662216.1 linkc.30+40794C>T intron_variant Intron 3 of 6 ENSP00000499467.1 A0A590UJK7
ENSG00000287856ENST00000653908.1 linkc.30+40794C>T intron_variant Intron 2 of 4 ENSP00000499669.1 A0A590UK27
ENSG00000287856ENST00000653198.1 linkn.433+40828C>T intron_variant Intron 4 of 7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000230
AC:
3
AN:
1302540
Hom.:
0
Cov.:
31
AF XY:
0.00000311
AC XY:
2
AN XY:
642268
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000355
Gnomad4 SAS exome
AF:
0.0000142
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000187
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.0000180
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3 Uncertain:1
Jul 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 82 of the EGLN1 protein (p.Ala82Val). This variant is present in population databases (rs771498926, gnomAD no frequency). This missense change has been observed in individual(s) with paraganglioma (PMID: 34309460). ClinVar contains an entry for this variant (Variation ID: 534224). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified Benign:1
Dec 27, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.46
T
M_CAP
Pathogenic
0.56
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.30
N
REVEL
Benign
0.13
Sift
Benign
0.34
T
Sift4G
Benign
0.26
T
Polyphen
0.0
B
Vest4
0.080
MutPred
0.16
Loss of relative solvent accessibility (P = 0.008);
MVP
0.69
MPC
1.7
ClinPred
0.084
T
GERP RS
-1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.041
gMVP
0.21

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: rs771498926; hg19: chr1-231557390; API