1-231421509-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022051.3(EGLN1):​c.380G>T​(p.Cys127Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000257 in 1,167,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C127S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1622963).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	NM_022051.3	MANE Select	c.380G>T	p.Cys127Phe	missense	Exon 1 of 5	NP_071334.1
	EGLN1	NM_001377260.1		c.380G>T	p.Cys127Phe	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.380G>T	p.Cys127Phe	missense	Exon 1 of 4	NP_001364190.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.380G>T	p.Cys127Phe	missense	Exon 1 of 5	ENSP00000355601.3
	ENSG00000287856	ENST00000662216.1		c.30+40929G>T		intron	N/A	ENSP00000499467.1
	EGLN1	ENST00000889867.1		c.380G>T	p.Cys127Phe	missense	Exon 1 of 6	ENSP00000559926.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000257 AC: 3 AN: 1167044 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 558980

African (AFR) AF: 0.00 AC: 0 AN: 22962

American (AMR) AF: 0.00 AC: 0 AN: 9002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15376

East Asian (EAS) AF: 0.0000371 AC: 1 AN: 26954

South Asian (SAS) AF: 0.00 AC: 0 AN: 35316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3872

European-Non Finnish (NFE) AF: 0.00000207 AC: 2 AN: 966998

Other (OTH) AF: 0.00 AC: 0 AN: 47382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.18	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.24
Sift	Benign	0.053	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.071
MutPred		0.23		Loss of catalytic residue at P126 (P = 0.0064)
MVP		0.13
MPC		1.6
ClinPred		0.098	T
GERP RS		3.3
PromoterAI		-0.067	Neutral
Varity_R		0.18
gMVP		0.31
Mutation Taster		=100/0	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: rs12097901; hg19: chr1-231557255;