rs531081279

Positions:

chr1-231421570-C-A

Variant summary

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

The NM_022051.3(EGLN1):c.319G>T(p.Ala107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,308,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. A107G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

EGLN1
NM_022051.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0340

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=0.032389164).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN1	NM_022051.3 linkuse as main transcript	c.319G>T	p.Ala107Ser	missense_variant	1/5	ENST00000366641.4	NP_071334.1	Q9GZT9-1R4SCQ0
EGLN1	NM_001377260.1 linkuse as main transcript	c.319G>T	p.Ala107Ser	missense_variant	1/4		NP_001364189.1
EGLN1	NM_001377261.1 linkuse as main transcript	c.319G>T	p.Ala107Ser	missense_variant	1/4		NP_001364190.1
EGLN1	XM_024447734.2 linkuse as main transcript	c.319G>T	p.Ala107Ser	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.319G>T	p.Ala107Ser	missense_variant	1/5	1	NM_022051.3	ENSP00000355601.3	Q9GZT9-1
ENSG00000287856	ENST00000662216.1 linkuse as main transcript	c.30+40868G>T		intron_variant				ENSP00000499467.1	A0A590UJK7
ENSG00000287856	ENST00000653908.1 linkuse as main transcript	c.30+40868G>T		intron_variant				ENSP00000499669.1	A0A590UK27
ENSG00000287856	ENST00000653198.1 linkuse as main transcript	n.433+40902G>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000389

AC:

AN:

1156822

Hom.:

Cov.:

AF XY:

0.0000323

AC XY:

AN XY:

557508

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00163

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000427

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151834

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.319G>T (p.A107S) alteration is located in exon 1 (coding exon 1) of the EGLN1 gene. This alteration results from a G to T substitution at nucleotide position 319, causing the alanine (A) at amino acid position 107 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Erythrocytosis, familial, 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 107 of the EGLN1 protein (p.Ala107Ser). This variant is present in population databases (rs531081279, gnomAD 0.06%). 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: 241416). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.6

DANN

Benign

0.97

DEOGEN2

Benign

0.19

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.41

MetaRNN

Benign

0.032

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.90

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.37

REVEL

Benign

0.085

Sift

Benign

0.77

Sift4G

Benign

0.69

Polyphen

0.050

Vest4

0.071

MutPred

0.18

Gain of glycosylation at A107 (P = 0.007);

MVP

0.56

MPC

1.7

ClinPred

0.089

GERP RS

1.2

Varity_R

0.069

gMVP

0.21

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