rs480902

Variant names:

• chr1-231395881-T-C
• rs480902
• NM_022051.3:c.892-21782A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022051.3(EGLN1):​c.892-21782A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 151,676 control chromosomes in the GnomAD database, including 32,990 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (32990 hom., cov: 29)
• Consequence: EGLN1 NM_022051.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.15
• Publications: 36 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: Genomics England PanelApp, Ambry Genetics, 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.892-21782A>G		intron_variant	Intron 1 of 4	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.892-21782A>G		intron_variant	Intron 1 of 3		NP_001364189.1
EGLN1	NM_001377261.1	c.892-21782A>G		intron_variant	Intron 1 of 3		NP_001364190.1
EGLN1	XM_024447734.2	c.892-21782A>G		intron_variant	Intron 1 of 2		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.892-21782A>G		intron_variant	Intron 1 of 4	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.31-21782A>G		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97670 AN: 151558 Hom.: 32988 Cov.: 29

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.752

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.677

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.644 AC: 97697 AN: 151676 Hom.: 32990 Cov.: 29 AF XY: 0.643 AC XY: 47648 AN XY: 74102

African (AFR) AF: 0.429 AC: 17737 AN: 41326

American (AMR) AF: 0.651 AC: 9906 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2635 AN: 3468

East Asian (EAS) AF: 0.561 AC: 2871 AN: 5122

South Asian (SAS) AF: 0.609 AC: 2930 AN: 4812

European-Finnish (FIN) AF: 0.733 AC: 7714 AN: 10530

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.759 AC: 51530 AN: 67884

Other (OTH) AF: 0.674 AC: 1421 AN: 2108

Alfa AF: 0.723 Hom.: 170000

Bravo AF: 0.631

Asia WGS AF: 0.582 AC: 2021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0090
DANN	Benign	0.36
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs480902; hg19: chr1-231531627; COSMIC: COSV64148603;