rs12097901

Positions:

• chr1-231421509-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000366641.4(EGLN1):​c.380G>C​(p.Cys127Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 1,318,298 control chromosomes in the GnomAD database, including 10,267 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C127F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2926 hom., cov: 32)
  • Exomes 𝑓: 0.081 (7341 hom.)
• Consequence: EGLN1 ENST00000366641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.27

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6285752E-5).
• BP6: Variant 1-231421509-C-G is Benign according to our data. Variant chr1-231421509-C-G is described in ClinVar as [Benign]. Clinvar id is 242640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.380G>C	p.Cys127Ser	missense_variant	1/5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.380G>C	p.Cys127Ser	missense_variant	1/4		NP_001364189.1
EGLN1	NM_001377261.1	c.380G>C	p.Cys127Ser	missense_variant	1/4		NP_001364190.1
EGLN1	XM_024447734.2	c.380G>C	p.Cys127Ser	missense_variant	1/3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.380G>C	p.Cys127Ser	missense_variant	1/5	1	NM_022051.3	ENSP00000355601	P1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23565 AN: 151282 Hom.: 2912 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0799

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.100 AC: 1165 AN: 11604 Hom.: 91 AF XY: 0.103 AC XY: 594 AN XY: 5770

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.510

Gnomad SAS exome AF: 0.328

Gnomad FIN exome AF: 0.0716

Gnomad NFE exome AF: 0.0939

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.0810 AC: 94529 AN: 1166910 Hom.: 7341 Cov.: 31 AF XY: 0.0825 AC XY: 46088 AN XY: 558896

Gnomad4 AFR exome AF: 0.322

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.0883

Gnomad4 EAS exome AF: 0.452

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.0754

Gnomad4 NFE exome AF: 0.0568

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.156 AC: 23608 AN: 151388 Hom.: 2926 Cov.: 32 AF XY: 0.159 AC XY: 11748 AN XY: 73998

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.0799

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.0772

Gnomad4 NFE AF: 0.0602

Gnomad4 OTH AF: 0.161

Alfa AF: 0.118 Hom.: 221

Bravo AF: 0.166

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0519 AC: 200

ExAC AF: 0.0935 AC: 731

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 30906831, 23666208, 25129147, 24711448, 28233034, 32377332) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 12, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.44
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.000016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.88	N
REVEL	Benign	0.21
Sift	Benign	0.73	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.0090
MutPred		0.28		Gain of glycosylation at C127 (P = 0.0016);
MPC		1.4
ClinPred		0.0015	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.081
gMVP		0.29

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: rs12097901; hg19: chr1-231557255; COSMIC: COSV64149723; COSMIC: COSV64149723;