19-40800457-G-A

Variant names:

• chr19-40800457-G-A
• rs11547373
• NM_080732.4:c.-116G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_080732.4(EGLN2):​c.-116G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,425,032 control chromosomes in the GnomAD database, including 88,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7791 hom., cov: 32)
  • Exomes 𝑓: 0.35 (80640 hom.)
• Consequence: EGLN2 NM_080732.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.534
• Publications: 16 publications found

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:44465): (RAB4B-EGLN2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RAB4B (RAB4B, member RAS oncogene family) and EGLN2 (egl nine homolog 2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-40800457-G-A is Benign according to our data. Variant chr19-40800457-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	NM_080732.4	MANE Select	c.-116G>A		5_prime_UTR	Exon 2 of 6	NP_542770.2	Q96KS0-1
	EGLN2	NM_053046.4		c.-116G>A		5_prime_UTR	Exon 2 of 6	NP_444274.1	Q96KS0-1
	RAB4B-EGLN2	NR_037791.1		n.933G>A		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGLN2	ENST00000303961.9	TSL:1 MANE Select	c.-116G>A		5_prime_UTR	Exon 2 of 6	ENSP00000307080.3	Q96KS0-1
	EGLN2	ENST00000406058.6	TSL:1	c.-116G>A		5_prime_UTR	Exon 2 of 6	ENSP00000385253.1	Q96KS0-1
	EGLN2	ENST00000593726.5	TSL:1	c.-116G>A		5_prime_UTR	Exon 1 of 5	ENSP00000469686.1	Q96KS0-1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43464 AN: 151830 Hom.: 7784 Cov.: 32

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.316

GnomAD4 exome AF: 0.351 AC: 447178 AN: 1273084 Hom.: 80640 Cov.: 25 AF XY: 0.353 AC XY: 218371 AN XY: 618942

African (AFR) AF: 0.0569 AC: 1601 AN: 28114

American (AMR) AF: 0.476 AC: 9993 AN: 20980

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 5440 AN: 18886

East Asian (EAS) AF: 0.383 AC: 13406 AN: 34964

South Asian (SAS) AF: 0.377 AC: 24378 AN: 64594

European-Finnish (FIN) AF: 0.359 AC: 10977 AN: 30580

Middle Eastern (MID) AF: 0.282 AC: 1016 AN: 3600

European-Non Finnish (NFE) AF: 0.356 AC: 362329 AN: 1018312

Other (OTH) AF: 0.340 AC: 18038 AN: 53054

GnomAD4 genome AF: 0.286 AC: 43482 AN: 151948 Hom.: 7791 Cov.: 32 AF XY: 0.289 AC XY: 21490 AN XY: 74286

African (AFR) AF: 0.0728 AC: 3019 AN: 41482

American (AMR) AF: 0.425 AC: 6491 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1030 AN: 3462

East Asian (EAS) AF: 0.371 AC: 1912 AN: 5150

South Asian (SAS) AF: 0.378 AC: 1818 AN: 4814

European-Finnish (FIN) AF: 0.358 AC: 3784 AN: 10556

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24233 AN: 67898

Other (OTH) AF: 0.321 AC: 677 AN: 2110

Alfa AF: 0.291 Hom.: 918

Bravo AF: 0.282

Asia WGS AF: 0.395 AC: 1372 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.6
DANN	Benign	0.92
PhyloP100		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11547373; hg19: chr19-41306362; COSMIC: COSV58279323; COSMIC: COSV58279323;