rs2808611

Variant names:

• chr1-231412734-A-G
• rs2808611
• NM_022051.3:c.891+8264T>C

Variant summary

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

The NM_022051.3(EGLN1):​c.891+8264T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,048 control chromosomes in the GnomAD database, including 14,425 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 0.42 (14425 hom., cov: 32)
• Consequence: EGLN1 NM_022051.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 11 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 (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.891+8264T>C		intron_variant	Intron 1 of 4	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.891+8264T>C		intron_variant	Intron 1 of 3		NP_001364189.1
EGLN1	NM_001377261.1	c.891+8264T>C		intron_variant	Intron 1 of 3		NP_001364190.1
EGLN1	XM_024447734.2	c.891+8264T>C		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.891+8264T>C		intron_variant	Intron 1 of 4	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.31-38635T>C		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64234 AN: 151930 Hom.: 14394 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.414

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

GnomAD4 genome AF: 0.423 AC: 64313 AN: 152048 Hom.: 14425 Cov.: 32 AF XY: 0.419 AC XY: 31145 AN XY: 74320

African (AFR) AF: 0.580 AC: 24042 AN: 41430

American (AMR) AF: 0.447 AC: 6827 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1294 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2263 AN: 5164

South Asian (SAS) AF: 0.424 AC: 2048 AN: 4826

European-Finnish (FIN) AF: 0.276 AC: 2922 AN: 10568

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23639 AN: 67984

Other (OTH) AF: 0.416 AC: 876 AN: 2108

Alfa AF: 0.378 Hom.: 34185

Bravo AF: 0.442

Asia WGS AF: 0.433 AC: 1508 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	4.8
DANN	Benign	0.67
PhyloP100		0.19
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: rs2808611; hg19: chr1-231548480;