1-231421530-G-T

Variant names:

• chr1-231421530-G-T
• rs796280222
• NM_022051.3:c.359C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022051.3(EGLN1):​c.359C>A​(p.Pro120Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P120L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.433
• Publications: 4 publications found

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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000287856 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22419116).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	NM_022051.3	MANE Select	c.359C>A	p.Pro120Gln	missense	Exon 1 of 5	NP_071334.1
	EGLN1	NM_001377260.1		c.359C>A	p.Pro120Gln	missense	Exon 1 of 4	NP_001364189.1
	EGLN1	NM_001377261.1		c.359C>A	p.Pro120Gln	missense	Exon 1 of 4	NP_001364190.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN1	ENST00000366641.4	TSL:1 MANE Select	c.359C>A	p.Pro120Gln	missense	Exon 1 of 5	ENSP00000355601.3
	ENSG00000287856	ENST00000662216.1		c.30+40908C>A		intron	N/A	ENSP00000499467.1
	ENSG00000287856	ENST00000653908.1		c.30+40908C>A		intron	N/A	ENSP00000499669.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1148600 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 549254

African (AFR) AF: 0.00 AC: 0 AN: 22776

American (AMR) AF: 0.00 AC: 0 AN: 8448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14886

East Asian (EAS) AF: 0.00 AC: 0 AN: 26198

South Asian (SAS) AF: 0.00 AC: 0 AN: 31860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957784

Other (OTH) AF: 0.00 AC: 0 AN: 46334

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151672 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74072

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.43
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.22
Sift	Benign	0.35	T
Sift4G	Benign	0.47	T
Polyphen		0.84	P
Vest4		0.11
MutPred		0.21		Loss of loop (P = 0.0022)
MVP		0.61
MPC		2.0
ClinPred		0.29	T
GERP RS		2.2
PromoterAI		0.0030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.38
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs796280222; hg19: chr1-231557276;