19-40800579-A-G

Position:

• chr19-40800579-A-G

Variant summary

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

The NM_080732.4(EGLN2):​c.7A>G​(p.Ser3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EGLN2 NM_080732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

Genes affected

EGLN2 (HGNC:14660): (egl-9 family hypoxia inducible factor 2) The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degration by prolyl hydroxylation. This gene encodes an enzyme responsible for this post-translational modification. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream RAB4B (RAB4B, member RAS oncogene family) gene. [provided by RefSeq, Feb 2011]

RAB4B-EGLN2 (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=0.15556192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGLN2	NM_080732.4	c.7A>G	p.Ser3Gly	missense_variant	2/6	ENST00000303961.9	NP_542770.2
RAB4B-EGLN2	NR_037791.1	n.1055A>G		non_coding_transcript_exon_variant	8/12
EGLN2	NM_053046.4	c.7A>G	p.Ser3Gly	missense_variant	2/6		NP_444274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGLN2	ENST00000303961.9	c.7A>G	p.Ser3Gly	missense_variant	2/6	1	NM_080732.4	ENSP00000307080	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445618 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717244

Gnomad4 AFR exome AF: 0.00

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2024

The p.S3G variant (also known as c.7A>G), located in coding exon 1 of the EGLN2 gene, results from an A to G substitution at nucleotide position 7. The serine at codon 3 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	.;T;T;T;T;.;.;.;.;.
Eigen	Benign	0.074
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.73	T;.;T;.;T;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;.;N;N;.;.;.;.;.
MutationTaster	Benign	0.72	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.22	.;N;.;N;.;.;.;.;.;.
REVEL	Benign	0.11
Sift	Pathogenic	0.0	.;D;.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;T;D;T;T;D;D;D;D;D
Polyphen		0.88	.;P;.;P;P;.;.;.;.;.
Vest4		0.27, 0.27, 0.19
MutPred		0.13		Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);Loss of phosphorylation at S3 (P = 0.0185);
MVP		0.51
MPC		0.52
ClinPred		0.55	D
GERP RS		4.0
Varity_R		0.18
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2083247442; hg19: chr19-41306484;