1-231421530-G-C

Variant names:

• chr1-231421530-G-C
• rs796280222
• NM_022051.3:c.359C>G

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.359C>G​(p.Pro120Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P120L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.433
• 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=0.21717948).

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.359C>G	p.Pro120Arg	missense	Exon 1 of 5	NP_071334.1
	EGLN1	NM_001377260.1		c.359C>G	p.Pro120Arg	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.359C>G	p.Pro120Arg	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.359C>G	p.Pro120Arg	missense	Exon 1 of 5	ENSP00000355601.3
	ENSG00000287856	ENST00000662216.1		c.30+40908C>G		intron	N/A	ENSP00000499467.1
	ENSG00000287856	ENST00000653908.1		c.30+40908C>G		intron	N/A	ENSP00000499669.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	0.085
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.43
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.22
Sift	Benign	0.41	T
Sift4G	Benign	0.47	T
Polyphen		0.72	P
Vest4		0.049
MutPred		0.29		Gain of MoRF binding (P = 5e-04)
MVP		0.61
MPC		2.2
ClinPred		0.39	T
GERP RS		2.2
PromoterAI		0.0050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.46
Mutation Taster		=91/9	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: rs796280222; hg19: chr1-231557276;