rs551207815

Variant names:

• chr1-231421578-G-A
• rs551207815
• NM_022051.3:c.311C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022051.3(EGLN1):​c.311C>T​(p.Ser104Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,312,802 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S104S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.463
• Publications: 2 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, Genomics England PanelApp, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040185213).
• BP6: Variant 1-231421578-G-A is Benign according to our data. Variant chr1-231421578-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407205.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00103 (156/151848) while in subpopulation AFR AF = 0.00357 (148/41490). AF 95% confidence interval is 0.0031. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 156 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.311C>T	p.Ser104Phe	missense	Exon 1 of 5	NP_071334.1	R4SCQ0
	EGLN1	NM_001377260.1		c.311C>T	p.Ser104Phe	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.311C>T	p.Ser104Phe	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.311C>T	p.Ser104Phe	missense	Exon 1 of 5	ENSP00000355601.3	Q9GZT9-1
	ENSG00000287856	ENST00000662216.1		c.30+40860C>T		intron	N/A	ENSP00000499467.1	A0A590UJK7
	EGLN1	ENST00000889867.1		c.311C>T	p.Ser104Phe	missense	Exon 1 of 6	ENSP00000559926.1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 151740 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000235 AC: 1 AN: 4256 AF XY: 0.000397

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 176 AN: 1160954 Hom.: 1 Cov.: 31 AF XY: 0.000129 AC XY: 72 AN XY: 560308

African (AFR) AF: 0.00421 AC: 97 AN: 23046

American (AMR) AF: 0.000117 AC: 1 AN: 8546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15246

East Asian (EAS) AF: 0.00 AC: 0 AN: 26592

South Asian (SAS) AF: 0.0000544 AC: 2 AN: 36734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3204

European-Non Finnish (NFE) AF: 0.0000638 AC: 62 AN: 971272

Other (OTH) AF: 0.000297 AC: 14 AN: 47168

GnomAD4 genome AF: 0.00103 AC: 156 AN: 151848 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74230

African (AFR) AF: 0.00357 AC: 148 AN: 41490

American (AMR) AF: 0.000262 AC: 4 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67866

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.00109

Asia WGS AF: 0.000292 AC: 1 AN: 3436

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Erythrocytosis, familial, 3 (1)
-	1	-	Hemoglobin, high altitude adaptation;C1853286:Erythrocytosis, familial, 3 (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.46
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.049	D
Sift4G	Uncertain	0.042	D
Polyphen		0.085	B
Vest4		0.11
MutPred		0.18		Loss of glycosylation at S104 (P = 0.0063)
MVP		0.61
MPC		1.8
ClinPred		0.092	T
GERP RS		1.1
PromoterAI		-0.034	Neutral
Varity_R		0.076
gMVP		0.22
Mutation Taster		=94/6	polymorphism

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: rs551207815; hg19: chr1-231557324;