rs551207815

Positions:

chr1-231421578-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022051.3(EGLN1):c.311C>T(p.Ser104Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,312,802 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S104S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.463

Variant links:

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 links:

ENSG00000287856 (HGNC:):

ENSG00000287856 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040185213).

BS2

High AC in GnomAd4 at 156 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN1	NM_022051.3 linkuse as main transcript	c.311C>T	p.Ser104Phe	missense_variant	1/5	ENST00000366641.4	NP_071334.1	Q9GZT9-1R4SCQ0
EGLN1	NM_001377260.1 linkuse as main transcript	c.311C>T	p.Ser104Phe	missense_variant	1/4		NP_001364189.1
EGLN1	NM_001377261.1 linkuse as main transcript	c.311C>T	p.Ser104Phe	missense_variant	1/4		NP_001364190.1
EGLN1	XM_024447734.2 linkuse as main transcript	c.311C>T	p.Ser104Phe	missense_variant	1/3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGLN1	ENST00000366641.4 linkuse as main transcript	c.311C>T	p.Ser104Phe	missense_variant	1/5	1	NM_022051.3	ENSP00000355601.3	Q9GZT9-1
ENSG00000287856	ENST00000662216.1 linkuse as main transcript	c.30+40860C>T		intron_variant				ENSP00000499467.1	A0A590UJK7
ENSG00000287856	ENST00000653908.1 linkuse as main transcript	c.30+40860C>T		intron_variant				ENSP00000499669.1	A0A590UK27
ENSG00000287856	ENST00000653198.1 linkuse as main transcript	n.433+40894C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

151740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000235

AC:

AN:

4256

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

2518

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

176

AN:

1160954

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

560308

show subpopulations

Gnomad4 AFR exome

AF:

0.00421

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000544

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000638

Gnomad4 OTH exome

AF:

0.000297

GnomAD4 genome

AF:

0.00103

AC:

156

AN:

151848

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.00357

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000569

Hom.:

Bravo

AF:

0.00109

Asia WGS

AF:

0.000292

AC:

AN:

3436

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Erythrocytosis, familial, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 104 of the EGLN1 protein (p.Ser104Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with EGLN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407205). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including hereditary erythrocytosis and pheochromocytoma (Oliveira et al., 2018; Ben Aim et al., 2019); This variant is associated with the following publications: (PMID: 29790589, 30877234) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.90

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.1

REVEL

Benign

0.10

Sift

Benign

0.049

Sift4G

Uncertain

0.042

Polyphen

0.085

Vest4

0.11

MutPred

0.18

Loss of glycosylation at S104 (P = 0.0063);

MVP

0.61

MPC

1.8

ClinPred

0.092

GERP RS

1.1

Varity_R

0.076

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over