1-231395730-T-G

Variant names:

• chr1-231395730-T-G
• rs2486732
• NM_022051.3:c.892-21631A>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.892-21631A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 152,018 control chromosomes in the GnomAD database, including 22,794 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 0.52 (22794 hom., cov: 32)
• Consequence: EGLN1 NM_022051.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.933
• Publications: 5 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.892-21631A>C		intron_variant	Intron 1 of 4	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.892-21631A>C		intron_variant	Intron 1 of 3		NP_001364189.1
EGLN1	NM_001377261.1	c.892-21631A>C		intron_variant	Intron 1 of 3		NP_001364190.1
EGLN1	XM_024447734.2	c.892-21631A>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.892-21631A>C		intron_variant	Intron 1 of 4	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.31-21631A>C		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79463 AN: 151900 Hom.: 22792 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.641

Gnomad OTH AF: 0.547

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

GnomAD4 genome AF: 0.523 AC: 79470 AN: 152018 Hom.: 22794 Cov.: 32 AF XY: 0.528 AC XY: 39239 AN XY: 74302

African (AFR) AF: 0.261 AC: 10807 AN: 41462

American (AMR) AF: 0.531 AC: 8109 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2107 AN: 3464

East Asian (EAS) AF: 0.554 AC: 2863 AN: 5166

South Asian (SAS) AF: 0.562 AC: 2709 AN: 4818

European-Finnish (FIN) AF: 0.699 AC: 7372 AN: 10554

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.641 AC: 43586 AN: 67958

Other (OTH) AF: 0.545 AC: 1152 AN: 2112

Alfa AF: 0.561 Hom.: 4001

Bravo AF: 0.500

Asia WGS AF: 0.545 AC: 1894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.42
DANN	Benign	0.44
PhyloP100		-0.93
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: rs2486732; hg19: chr1-231531476; COSMIC: COSV64148598;