NM_022051.3:c.380G>C

Variant names:

• chr1-231421509-C-G
• rs12097901
• NM_022051.3:c.380G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022051.3(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. 15/21 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. C127Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2926 hom., cov: 32)
  • Exomes 𝑓: 0.081 (7341 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.27
• Publications: 66 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 -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 VariationId 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.

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.380G>C	p.Cys127Ser	missense	Exon 1 of 5	NP_071334.1
	EGLN1	NM_001377260.1		c.380G>C	p.Cys127Ser	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.380G>C	p.Cys127Ser	missense	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.380G>C	p.Cys127Ser	missense	Exon 1 of 5	ENSP00000355601.3
	ENSG00000287856	ENST00000662216.1		c.30+40929G>C		intron	N/A	ENSP00000499467.1
	EGLN1	ENST00000889867.1		c.380G>C	p.Cys127Ser	missense	Exon 1 of 6	ENSP00000559926.1

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

GnomAD2 exomes AF: 0.100 AC: 1165 AN: 11604 AF XY: 0.103

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 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

African (AFR) AF: 0.322 AC: 7402 AN: 22958

American (AMR) AF: 0.144 AC: 1292 AN: 9002

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 1357 AN: 15376

East Asian (EAS) AF: 0.452 AC: 12169 AN: 26950

South Asian (SAS) AF: 0.236 AC: 8322 AN: 35252

European-Finnish (FIN) AF: 0.0754 AC: 2952 AN: 39164

Middle Eastern (MID) AF: 0.103 AC: 397 AN: 3872

European-Non Finnish (NFE) AF: 0.0568 AC: 54903 AN: 966956

Other (OTH) AF: 0.121 AC: 5735 AN: 47380

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

African (AFR) AF: 0.307 AC: 12657 AN: 41228

American (AMR) AF: 0.135 AC: 2056 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0799 AC: 277 AN: 3466

East Asian (EAS) AF: 0.443 AC: 2237 AN: 5046

South Asian (SAS) AF: 0.230 AC: 1109 AN: 4822

European-Finnish (FIN) AF: 0.0772 AC: 808 AN: 10464

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0602 AC: 4084 AN: 67818

Other (OTH) AF: 0.161 AC: 339 AN: 2102

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Erythrocytosis, familial, 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.3
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
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.081
gMVP		0.29
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: rs12097901; hg19: chr1-231557255; COSMIC: COSV64149723; COSMIC: COSV64149723;