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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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.

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.471G>C	p.Gln157His	missense	Exon 1 of 5	NP_071334.1	R4SCQ0
	EGLN1	NM_001377260.1		c.471G>C	p.Gln157His	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.471G>C	p.Gln157His	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.471G>C	p.Gln157His	missense	Exon 1 of 5	ENSP00000355601.3	Q9GZT9-1
	ENSG00000287856	ENST00000662216.1		c.30+41020G>C		intron	N/A	ENSP00000499467.1	A0A590UJK7
	EGLN1	ENST00000889867.1		c.471G>C	p.Gln157His	missense	Exon 1 of 6	ENSP00000559926.1

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

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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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;