dbSNP rs531081279: EGLN1:p.Ala107Ser (chr1-231421570-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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

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

Conservation

PhyloP100: 0.0340

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

erythrocytosis, familial, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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

EGLN1 links:

ENSG00000287856 (HGNC:):

ENSG00000287856 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032389164).

BP6

Variant 1-231421570-C-A is Benign according to our data. Variant chr1-231421570-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241416.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000395 (6/151834) while in subpopulation EAS AF = 0.00117 (6/5128). AF 95% confidence interval is 0.000509. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 6 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGLN1	NM_022051.3	MANE Select	c.319G>T	p.Ala107Ser	missense	Exon 1 of 5	NP_071334.1	R4SCQ0
EGLN1	NM_001377260.1		c.319G>T	p.Ala107Ser	missense	Exon 1 of 4	NP_001364189.1
EGLN1	NM_001377261.1		c.319G>T	p.Ala107Ser	missense	Exon 1 of 4	NP_001364190.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.319G>T	p.Ala107Ser	missense	Exon 1 of 5	ENSP00000355601.3	Q9GZT9-1
ENSG00000287856	ENST00000662216.1		c.30+40868G>T		intron	N/A	ENSP00000499467.1	A0A590UJK7
EGLN1	ENST00000889867.1		c.319G>T	p.Ala107Ser	missense	Exon 1 of 6	ENSP00000559926.1

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

African (AFR)

AF:

0.00

AC:

AN:

22962

American (AMR)

AF:

0.00

AC:

AN:

8464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15138

East Asian (EAS)

AF:

0.00163

AC:

AN:

26458

South Asian (SAS)

AF:

0.00

AC:

AN:

35664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3206

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

967922

Other (OTH)

AF:

0.0000427

AC:

AN:

46892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151834

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41498

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00117

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Erythrocytosis, familial, 3 (1)

Hemoglobin, high altitude adaptation;C1853286:Erythrocytosis, familial, 3 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.6

(source)

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

PhyloP100

0.034

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

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.069

gMVP

0.21

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over