EGLN1 p.Asp4Glu

Variant names:

• chr1-231421877-G-T
• NM_022051.3:c.12C>A
• EGLN1 p.Asp4Glu

Your query was ambiguous. Multiple possible variants found:

• chr1-231421877-G-T
• chr1-231421877-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022051.3(EGLN1):​c.12C>A​(p.Asp4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D4G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.787
• Publications: 0 publications found

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: Ambry Genetics, Genomics England PanelApp, 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

ENSG00000287856 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1497814).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022051.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	NM_022051.3	MANE Select	c.12C>A	p.Asp4Glu	missense	Exon 1 of 5	NP_071334.1	R4SCQ0
	EGLN1	NM_001377260.1		c.12C>A	p.Asp4Glu	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.12C>A	p.Asp4Glu	missense	Exon 1 of 4	NP_001364190.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.12C>A	p.Asp4Glu	missense	Exon 1 of 5	ENSP00000355601.3	Q9GZT9-1
	ENSG00000287856	ENST00000662216.1		c.30+40561C>A		intron	N/A	ENSP00000499467.1	A0A590UJK7
	EGLN1	ENST00000889867.1		c.12C>A	p.Asp4Glu	missense	Exon 1 of 6	ENSP00000559926.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1336528 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 662314

African (AFR) AF: 0.00 AC: 0 AN: 27656

American (AMR) AF: 0.00 AC: 0 AN: 29642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23178

East Asian (EAS) AF: 0.00 AC: 0 AN: 30272

South Asian (SAS) AF: 0.00 AC: 0 AN: 73374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3874

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1059690

Other (OTH) AF: 0.00 AC: 0 AN: 55004

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.79
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.070	N
REVEL	Benign	0.27
Sift	Benign	0.31	T
Sift4G	Benign	0.086	T
PromoterAI		0.11	Neutral
Varity_R		0.15
gMVP		0.15
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-231557623;