rs186996510

Positions:

• chr1-231421877-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022051.3(EGLN1):​c.12C>G​(p.Asp4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,488,446 control chromosomes in the GnomAD database, including 63 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D4G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.787

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]

ENSG00000287856 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003653556).
• BP6: Variant 1-231421877-G-C is Benign according to our data. Variant chr1-231421877-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 225682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00141 (214/151930) while in subpopulation EAS AF= 0.0319 (163/5110). AF 95% confidence interval is 0.0279. There are 12 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.12C>G	p.Asp4Glu	missense_variant	1/5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.12C>G	p.Asp4Glu	missense_variant	1/4		NP_001364189.1
EGLN1	NM_001377261.1	c.12C>G	p.Asp4Glu	missense_variant	1/4		NP_001364190.1
EGLN1	XM_024447734.2	c.12C>G	p.Asp4Glu	missense_variant	1/3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.12C>G	p.Asp4Glu	missense_variant	1/5	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.30+40561C>G		intron_variant				ENSP00000499467.1
ENSG00000287856	ENST00000653908.1	c.30+40561C>G		intron_variant				ENSP00000499669.1
ENSG00000287856	ENST00000653198.1	n.433+40595C>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 151820 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00256 AC: 287 AN: 112318 Hom.: 3 AF XY: 0.00223 AC XY: 145 AN XY: 64930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0202

Gnomad SAS exome AF: 0.00169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.00143

GnomAD4 exome AF: 0.00147 AC: 1970 AN: 1336516 Hom.: 51 Cov.: 31 AF XY: 0.00150 AC XY: 993 AN XY: 662306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0451

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.00231

GnomAD4 genome AF: 0.00141 AC: 214 AN: 151930 Hom.: 12 Cov.: 32 AF XY: 0.00162 AC XY: 120 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0319

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.00181

ExAC AF: 0.00197 AC: 217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Erythrocytosis, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2020

This alteration is classified as 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. -

EGLN1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.070	N
REVEL	Benign	0.26
Sift	Benign	0.31	T
Sift4G	Benign	0.086	T
Polyphen		0.010	B
Vest4		0.0070
MutPred		0.099		Gain of solvent accessibility (P = 0.0808);
MVP		0.47
MPC		1.6
ClinPred		0.023	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.15

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: rs186996510; hg19: chr1-231557623;