rs555121182

Variant names:

• chr1-231421769-G-A
• rs555121182
• NM_022051.3:c.120C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_022051.3(EGLN1):​c.120C>T​(p.Phe40Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.000428 in 1,557,014 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (6 hom.)
• Consequence: EGLN1 NM_022051.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.24
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-231421769-G-A is Benign according to our data. Variant chr1-231421769-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000447 (68/151964) while in subpopulation EAS AF = 0.0113 (58/5120). AF 95% confidence interval is 0.009. There are 1 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 68 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022051.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	NM_022051.3	MANE Select	c.120C>T	p.Phe40Phe	synonymous	Exon 1 of 5	NP_071334.1
	EGLN1	NM_001377260.1		c.120C>T	p.Phe40Phe	synonymous	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.120C>T	p.Phe40Phe	synonymous	Exon 1 of 4	NP_001364190.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.120C>T	p.Phe40Phe	synonymous	Exon 1 of 5	ENSP00000355601.3
	ENSG00000287856	ENST00000662216.1		c.30+40669C>T		intron	N/A	ENSP00000499467.1
	EGLN1	ENST00000889867.1		c.120C>T	p.Phe40Phe	synonymous	Exon 1 of 6	ENSP00000559926.1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 151856 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00119 AC: 213 AN: 179634 AF XY: 0.00108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000426 AC: 598 AN: 1405050 Hom.: 6 Cov.: 31 AF XY: 0.000470 AC XY: 328 AN XY: 697968

African (AFR) AF: 0.0000331 AC: 1 AN: 30218

American (AMR) AF: 0.00 AC: 0 AN: 40394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24980

East Asian (EAS) AF: 0.0118 AC: 422 AN: 35800

South Asian (SAS) AF: 0.00160 AC: 130 AN: 81050

European-Finnish (FIN) AF: 0.0000271 AC: 1 AN: 36912

Middle Eastern (MID) AF: 0.00123 AC: 5 AN: 4056

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1093240

Other (OTH) AF: 0.000479 AC: 28 AN: 58400

GnomAD4 genome AF: 0.000447 AC: 68 AN: 151964 Hom.: 1 Cov.: 32 AF XY: 0.000525 AC XY: 39 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41516

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0113 AC: 58 AN: 5120

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67900

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.00671 AC: 23 AN: 3442

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Erythrocytosis, familial, 3 (2)
-	-	1	EGLN1-related disorder (1)
-	-	1	Hemoglobin, high altitude adaptation;C1853286:Erythrocytosis, familial, 3 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		4.2
Mutation Taster		=100/0	polymorphism

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: rs555121182; hg19: chr1-231557515; COSMIC: COSV64148118; COSMIC: COSV64148118;