NM_000799.4:c.246+265G>A

Variant names:

• chr7-100722313-G-A
• rs507392
• NM_000799.4:c.246+265G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000799.4(EPO):​c.246+265G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 151,652 control chromosomes in the GnomAD database, including 29,406 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29406 hom., cov: 29)
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 28 publications found

Genes affected

EPO (HGNC:3415): (erythropoietin) This gene encodes a secreted, glycosylated cytokine composed of four alpha helical bundles. The encoded protein is mainly synthesized in the kidney, secreted into the blood plasma, and binds to the erythropoietin receptor to promote red blood cell production, or erythropoiesis, in the bone marrow. Expression of this gene is upregulated under hypoxic conditions, in turn leading to increased erythropoiesis and enhanced oxygen-carrying capacity of the blood. Expression of this gene has also been observed in brain and in the eye, and elevated expression levels have been observed in diabetic retinopathy and ocular hypertension. Recombinant forms of the encoded protein exhibit neuroprotective activity against a variety of potential brain injuries, as well as antiapoptotic functions in several tissue types, and have been used in the treatment of anemia and to enhance the efficacy of cancer therapies. [provided by RefSeq, Aug 2017]

EPO Gene-Disease associations (from GenCC):

• erythrocytosis, familial, 5

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Diamond-Blackfan anemia-like

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000799.4. 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
	EPO	NM_000799.4	MANE Select	c.246+265G>A		intron	N/A	NP_000790.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPO	ENST00000252723.3	TSL:1 MANE Select	c.246+265G>A		intron	N/A	ENSP00000252723.2

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94052 AN: 151532 Hom.: 29384 Cov.: 29

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.667

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.621 AC: 94120 AN: 151652 Hom.: 29406 Cov.: 29 AF XY: 0.625 AC XY: 46236 AN XY: 74028

African (AFR) AF: 0.623 AC: 25744 AN: 41344

American (AMR) AF: 0.704 AC: 10720 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2485 AN: 3468

East Asian (EAS) AF: 0.790 AC: 4042 AN: 5114

South Asian (SAS) AF: 0.644 AC: 3089 AN: 4800

European-Finnish (FIN) AF: 0.527 AC: 5510 AN: 10462

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40473 AN: 67936

Other (OTH) AF: 0.671 AC: 1411 AN: 2104

Alfa AF: 0.609 Hom.: 37601

Bravo AF: 0.634

Asia WGS AF: 0.698 AC: 2430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.4
DANN	Benign	0.38
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs507392; hg19: chr7-100319936;