1-231421613-C-T

Variant names:

• chr1-231421613-C-T
• rs992728216
• NM_022051.3:c.276G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_022051.3(EGLN1):​c.276G>A​(p.Glu92Glu) variant causes a synonymous 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EGLN1 NM_022051.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.502
• 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: 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-231421613-C-T is Benign according to our data. Variant chr1-231421613-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3507204.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.502 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	NM_022051.3	MANE Select	c.276G>A	p.Glu92Glu	synonymous	Exon 1 of 5	NP_071334.1	R4SCQ0
	EGLN1	NM_001377260.1		c.276G>A	p.Glu92Glu	synonymous	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.276G>A	p.Glu92Glu	synonymous	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.276G>A	p.Glu92Glu	synonymous	Exon 1 of 5	ENSP00000355601.3	Q9GZT9-1
	ENSG00000287856	ENST00000662216.1		c.30+40825G>A		intron	N/A	ENSP00000499467.1	A0A590UJK7
	EGLN1	ENST00000889867.1		c.276G>A	p.Glu92Glu	synonymous	Exon 1 of 6	ENSP00000559926.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1198206 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 584020

African (AFR) AF: 0.00 AC: 0 AN: 23650

American (AMR) AF: 0.00 AC: 0 AN: 9964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16294

East Asian (EAS) AF: 0.00 AC: 0 AN: 27188

South Asian (SAS) AF: 0.00 AC: 0 AN: 46866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3352

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 993054

Other (OTH) AF: 0.00 AC: 0 AN: 48932

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.4
DANN	Benign	0.97
PhyloP100		-0.50
PromoterAI		0.028	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: rs992728216; hg19: chr1-231557359;