1-231421570-C-T

Variant names:

• chr1-231421570-C-T
• NM_022051.3:c.319G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022051.3(EGLN1):​c.319G>A​(p.Ala107Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000173 in 1,156,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. A107S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: EGLN1 NM_022051.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12247294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGLN1	NM_022051.3	c.319G>A	p.Ala107Thr	missense_variant	Exon 1 of 5	ENST00000366641.4	NP_071334.1
EGLN1	NM_001377260.1	c.319G>A	p.Ala107Thr	missense_variant	Exon 1 of 4		NP_001364189.1
EGLN1	NM_001377261.1	c.319G>A	p.Ala107Thr	missense_variant	Exon 1 of 4		NP_001364190.1
EGLN1	XM_024447734.2	c.319G>A	p.Ala107Thr	missense_variant	Exon 1 of 3		XP_024303502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGLN1	ENST00000366641.4	c.319G>A	p.Ala107Thr	missense_variant	Exon 1 of 5	1	NM_022051.3	ENSP00000355601.3
ENSG00000287856	ENST00000662216.1	c.30+40868G>A		intron_variant	Intron 3 of 6			ENSP00000499467.1
ENSG00000287856	ENST00000653908.1	c.30+40868G>A		intron_variant	Intron 2 of 4			ENSP00000499669.1
ENSG00000287856	ENST00000653198.1	n.433+40902G>A		intron_variant	Intron 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000173 AC: 2 AN: 1156822 Hom.: 0 Cov.: 31 AF XY: 0.00000179 AC XY: 1 AN XY: 557508

Gnomad4 AFR exome AF: 0.0000436

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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.33	N
REVEL	Benign	0.065
Sift	Benign	0.56	T
Sift4G	Benign	0.55	T
Polyphen		0.10	B
Vest4		0.033
MutPred		0.19		Gain of glycosylation at A107 (P = 0.0122);
MVP		0.48
MPC		1.7
ClinPred		0.082	T
GERP RS		1.2
Varity_R		0.054
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-231557316;