chr1-231421484-G-C

Variant names:

• chr1-231421484-G-C
• rs781566823
• NM_022051.3:c.405C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_022051.3(EGLN1):​c.405C>G​(p.Gly135Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000828 in 1,207,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G135G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: EGLN1 NM_022051.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.

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.405C>G	p.Gly135Gly	synonymous	Exon 1 of 5	NP_071334.1
	EGLN1	NM_001377260.1		c.405C>G	p.Gly135Gly	synonymous	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.405C>G	p.Gly135Gly	synonymous	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.405C>G	p.Gly135Gly	synonymous	Exon 1 of 5	ENSP00000355601.3
	ENSG00000287856	ENST00000662216.1		c.30+40954C>G		intron	N/A	ENSP00000499467.1
	ENSG00000287856	ENST00000653908.1		c.30+40954C>G		intron	N/A	ENSP00000499669.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.28e-7 AC: 1 AN: 1207432 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 582276

African (AFR) AF: 0.00 AC: 0 AN: 23466

American (AMR) AF: 0.00 AC: 0 AN: 10720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16150

East Asian (EAS) AF: 0.00 AC: 0 AN: 28354

South Asian (SAS) AF: 0.00 AC: 0 AN: 44004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4330

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 990010

Other (OTH) AF: 0.00 AC: 0 AN: 49166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.2
DANN	Benign	0.56
PhyloP100		0.0050
PromoterAI		-0.13	Neutral
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: rs781566823; hg19: chr1-231557230;