rs992728216

chr1-231421613-C-Gchr1-231421613-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_022051.3(EGLN1):c.276G>C(p.Glu92Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,349,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E92A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.502

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10412976).
• BP6: Variant 1-231421613-C-G is Benign according to our data. Variant chr1-231421613-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435034.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGLN1	NM_022051.3	c.276G>C	p.Glu92Asp	missense_variant	1/5	ENST00000366641.4
EGLN1	NM_001377260.1	c.276G>C	p.Glu92Asp	missense_variant	1/4
EGLN1	NM_001377261.1	c.276G>C	p.Glu92Asp	missense_variant	1/4
EGLN1	XM_024447734.2	c.276G>C	p.Glu92Asp	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGLN1	ENST00000366641.4	c.276G>C	p.Glu92Asp	missense_variant	1/5	1	NM_022051.3	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151778 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000835 AC: 10 AN: 1198206 Hom.: 0 Cov.: 31 AF XY: 0.0000120 AC XY: 7 AN XY: 584020

Gnomad4 AFR exome AF: 0.000423

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151778 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74142

Gnomad4 AFR AF: 0.000387

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Erythrocytosis, familial, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 14, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 435034). This variant has not been reported in the literature in individuals affected with EGLN1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 92 of the EGLN1 protein (p.Glu92Asp). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.6
Dann	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.17
Sift	Benign	0.38	T
Sift4G	Benign	0.36	T
Polyphen		0.21	B
Vest4		0.057
MutPred		0.094		Gain of loop (P = 0.0502);
MVP		0.55
MPC		1.3
ClinPred		0.070	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.030
gMVP		0.23

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

Other links and lift over

dbSNP: rs992728216; hg19: chr1-231557359;