chr1-231421418-C-T

Variant names:

• chr1-231421418-C-T
• rs61750991
• NM_022051.3:c.471G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_022051.3(EGLN1):​c.471G>A​(p.Gln157Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,434,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000011 (0 hom.)
• Consequence: EGLN1 NM_022051.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0620
• Publications: 14 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-231421418-C-T is Benign according to our data. Variant chr1-231421418-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1742651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.062 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.471G>A	p.Gln157Gln	synonymous_variant	Exon 1 of 5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.471G>A	p.Gln157Gln	synonymous_variant	Exon 1 of 4		NP_001364189.1
EGLN1	NM_001377261.1	c.471G>A	p.Gln157Gln	synonymous_variant	Exon 1 of 4		NP_001364190.1
EGLN1	XM_024447734.2	c.471G>A	p.Gln157Gln	synonymous_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.471G>A	p.Gln157Gln	synonymous_variant	Exon 1 of 5	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.30+41020G>A		intron_variant	Intron 3 of 6			ENSP00000499467.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000472 AC: 1 AN: 211750 AF XY: 0.00000852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1434492 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 10 AN XY: 709772

African (AFR) AF: 0.00 AC: 0 AN: 32636

American (AMR) AF: 0.00 AC: 0 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25204

East Asian (EAS) AF: 0.00 AC: 0 AN: 38768

South Asian (SAS) AF: 0.00 AC: 0 AN: 84390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1095578

Other (OTH) AF: 0.0000170 AC: 1 AN: 58924

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 08, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Erythrocytosis, familial, 3 Benign:1

Mar 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.1
DANN	Benign	0.84
PhyloP100		0.062
PromoterAI		-0.0014	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: rs61750991; hg19: chr1-231557164;