rs2066140

Variant names:

• chr1-231368565-G-C
• rs2066140
• NM_022051.3:c.1149-929C>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.1149-929C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,038 control chromosomes in the GnomAD database, including 24,268 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 0.55 (24268 hom., cov: 32)
• Consequence: EGLN1 NM_022051.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 13 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.1149-929C>G		intron_variant	Intron 3 of 4	ENST00000366641.4	NP_071334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.1149-929C>G		intron_variant	Intron 3 of 4	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.288-929C>G		intron_variant	Intron 5 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 83021 AN: 151920 Hom.: 24263 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.564

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

GnomAD4 genome AF: 0.546 AC: 83047 AN: 152038 Hom.: 24268 Cov.: 32 AF XY: 0.551 AC XY: 40966 AN XY: 74304

African (AFR) AF: 0.318 AC: 13170 AN: 41464

American (AMR) AF: 0.542 AC: 8282 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2169 AN: 3472

East Asian (EAS) AF: 0.559 AC: 2893 AN: 5172

South Asian (SAS) AF: 0.573 AC: 2762 AN: 4822

European-Finnish (FIN) AF: 0.710 AC: 7484 AN: 10544

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44294 AN: 67976

Other (OTH) AF: 0.563 AC: 1188 AN: 2112

Alfa AF: 0.594 Hom.: 3498

Bravo AF: 0.524

Asia WGS AF: 0.561 AC: 1950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.53
PhyloP100		1.2
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: rs2066140; hg19: chr1-231504311;