rs143991968

Positions:

• chr1-231370597-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The ENST00000366641.4(EGLN1):​c.1113C>T​(p.Arg371=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,020 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 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: EGLN1 ENST00000366641.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-231370597-G-A is Benign according to our data. Variant chr1-231370597-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 296186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-231370597-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BS2: High AC in GnomAd4 at 306 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.1113C>T	p.Arg371=	synonymous_variant	3/5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.1113C>T	p.Arg371=	synonymous_variant	3/4		NP_001364189.1
EGLN1	NM_001377261.1	c.1012-2961C>T		intron_variant			NP_001364190.1
EGLN1	XM_024447734.2	c.1012-2961C>T		intron_variant			XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.1113C>T	p.Arg371=	synonymous_variant	3/5	1	NM_022051.3	ENSP00000355601	P1

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00175 AC: 441 AN: 251382 Hom.: 2 AF XY: 0.00160 AC XY: 218 AN XY: 135848

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00250 AC: 3658 AN: 1461770 Hom.: 7 Cov.: 32 AF XY: 0.00245 AC XY: 1784 AN XY: 727198

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00308

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74450

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00177

EpiCase AF: 0.00180

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Erythrocytosis, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

EGLN1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.2
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs143991968; hg19: chr1-231506343; COSMIC: COSV64149878;