1-231421530-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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]

ENSG00000287856 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21717948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.359C>G	p.Pro120Arg	missense_variant	Exon 1 of 5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.359C>G	p.Pro120Arg	missense_variant	Exon 1 of 4		NP_001364189.1
EGLN1	NM_001377261.1	c.359C>G	p.Pro120Arg	missense_variant	Exon 1 of 4		NP_001364190.1
EGLN1	XM_024447734.2	c.359C>G	p.Pro120Arg	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.359C>G	p.Pro120Arg	missense_variant	Exon 1 of 5	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.30+40908C>G		intron_variant	Intron 3 of 6			ENSP00000499467.1
ENSG00000287856	ENST00000653908.1	c.30+40908C>G		intron_variant	Intron 2 of 4			ENSP00000499669.1
ENSG00000287856	ENST00000653198.1	n.433+40942C>G		intron_variant	Intron 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P120R variant (also known as c.359C>G), located in coding exon 1 of the EGLN1 gene, results from a C to G substitution at nucleotide position 359. The proline at codon 120 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.46

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-231557276;