1-231399838-C-T

Variant names:

• chr1-231399838-C-T
• rs2486729
• NM_022051.3:c.891+21160G>A

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+21160G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,850 control chromosomes in the GnomAD database, including 24,198 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 (24198 hom., cov: 31)
• Consequence: EGLN1 NM_022051.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 21 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=-0.9).
• 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.891+21160G>A		intron_variant	Intron 1 of 4	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.891+21160G>A		intron_variant	Intron 1 of 3		NP_001364189.1
EGLN1	NM_001377261.1	c.891+21160G>A		intron_variant	Intron 1 of 3		NP_001364190.1
EGLN1	XM_024447734.2	c.891+21160G>A		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+21160G>A		intron_variant	Intron 1 of 4	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.31-25739G>A		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82753 AN: 151736 Hom.: 24192 Cov.: 31

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.565

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

GnomAD4 genome AF: 0.545 AC: 82780 AN: 151850 Hom.: 24198 Cov.: 31 AF XY: 0.550 AC XY: 40826 AN XY: 74184

African (AFR) AF: 0.315 AC: 13037 AN: 41418

American (AMR) AF: 0.542 AC: 8267 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2169 AN: 3468

East Asian (EAS) AF: 0.548 AC: 2787 AN: 5082

South Asian (SAS) AF: 0.573 AC: 2753 AN: 4802

European-Finnish (FIN) AF: 0.710 AC: 7499 AN: 10558

Middle Eastern (MID) AF: 0.640 AC: 187 AN: 292

European-Non Finnish (NFE) AF: 0.652 AC: 44277 AN: 67952

Other (OTH) AF: 0.564 AC: 1185 AN: 2102

Alfa AF: 0.581 Hom.: 41842

Bravo AF: 0.523

Asia WGS AF: 0.557 AC: 1936 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.54
PhyloP100		-0.12
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: rs2486729; hg19: chr1-231535584; COSMIC: COSV107466947;