rs61750991

Variant names:

• chr1-231421418-C-G
• rs61750991
• NM_022051.3:c.471G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-231421418-C-G
• chr1-231421418-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022051.3(EGLN1):​c.471G>C​(p.Gln157His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,586,690 control chromosomes in the GnomAD database, including 650 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. Q157R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 32)
  • Exomes 𝑓: 0.026 (617 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0620
• Publications: 14 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=0.0025871098).
• BP6: Variant 1-231421418-C-G is Benign according to our data. Variant chr1-231421418-C-G is described in ClinVar as Benign. ClinVar VariationId is 241417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0175 (2666/152224) while in subpopulation NFE AF = 0.0275 (1868/67990). AF 95% confidence interval is 0.0264. There are 33 homozygotes in GnomAd4. There are 1256 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2666 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.471G>C	p.Gln157His	missense_variant	Exon 1 of 5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.471G>C	p.Gln157His	missense_variant	Exon 1 of 4		NP_001364189.1
EGLN1	NM_001377261.1	c.471G>C	p.Gln157His	missense_variant	Exon 1 of 4		NP_001364190.1
EGLN1	XM_024447734.2	c.471G>C	p.Gln157His	missense_variant	Exon 1 of 3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.471G>C	p.Gln157His	missense_variant	Exon 1 of 5	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.30+41020G>C		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2666 AN: 152108 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0399

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0176 AC: 3729 AN: 211750 AF XY: 0.0177

Gnomad AFR exome AF: 0.00368

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.00703

Gnomad EAS exome AF: 0.000121

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.0270

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0256 AC: 36790 AN: 1434466 Hom.: 617 Cov.: 31 AF XY: 0.0248 AC XY: 17578 AN XY: 709758

African (AFR) AF: 0.00294 AC: 96 AN: 32636

American (AMR) AF: 0.00657 AC: 280 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 142 AN: 25202

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38768

South Asian (SAS) AF: 0.00288 AC: 243 AN: 84390

European-Finnish (FIN) AF: 0.0447 AC: 2264 AN: 50684

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5686

European-Non Finnish (NFE) AF: 0.0297 AC: 32523 AN: 1095560

Other (OTH) AF: 0.0209 AC: 1231 AN: 58924

GnomAD4 genome AF: 0.0175 AC: 2666 AN: 152224 Hom.: 33 Cov.: 32 AF XY: 0.0169 AC XY: 1256 AN XY: 74432

African (AFR) AF: 0.00455 AC: 189 AN: 41562

American (AMR) AF: 0.00608 AC: 93 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5146

South Asian (SAS) AF: 0.00372 AC: 18 AN: 4834

European-Finnish (FIN) AF: 0.0399 AC: 423 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0275 AC: 1868 AN: 67990

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0229 Hom.: 15

Bravo AF: 0.0145

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.00456 AC: 17

ESP6500EA AF: 0.0213 AC: 157

ExAC AF: 0.0152 AC: 1770

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EGLN1: BS1, BS2 -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Erythrocytosis, familial, 3 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.062
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.22	T
Polyphen		0.29	B
Vest4		0.032
MutPred		0.16		Loss of helix (P = 0.028);
MPC		1.3
ClinPred		0.0016	T
GERP RS		-2.4
PromoterAI		-0.031	Neutral
Varity_R		0.029
gMVP		0.38
Mutation Taster		=94/6	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: rs61750991; hg19: chr1-231557164; COSMIC: COSV107466854; COSMIC: COSV107466854;