NM_000799.4:c.247-66G>A

Variant names:

• chr7-100722598-G-A
• rs7789679
• NM_000799.4:c.247-66G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000799.4(EPO):​c.247-66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0712 in 1,404,506 control chromosomes in the GnomAD database, including 4,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (306 hom., cov: 32)
  • Exomes 𝑓: 0.074 (3767 hom.)
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.69
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 7-100722598-G-A is Benign according to our data. Variant chr7-100722598-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0756 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPO	NM_000799.4	MANE Select	c.247-66G>A		intron	N/A	NP_000790.2	G9JKG7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPO	ENST00000252723.3	TSL:1 MANE Select	c.247-66G>A		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7832 AN: 152162 Hom.: 307 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0774

Gnomad OTH AF: 0.0589

GnomAD4 exome AF: 0.0736 AC: 92121 AN: 1252226 Hom.: 3767 AF XY: 0.0738 AC XY: 45737 AN XY: 619846

African (AFR) AF: 0.0141 AC: 392 AN: 27806

American (AMR) AF: 0.0334 AC: 954 AN: 28572

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 2373 AN: 19398

East Asian (EAS) AF: 0.000105 AC: 4 AN: 38276

South Asian (SAS) AF: 0.0725 AC: 4974 AN: 68614

European-Finnish (FIN) AF: 0.0486 AC: 2392 AN: 49176

Middle Eastern (MID) AF: 0.0742 AC: 259 AN: 3492

European-Non Finnish (NFE) AF: 0.0800 AC: 77188 AN: 964652

Other (OTH) AF: 0.0686 AC: 3585 AN: 52240

GnomAD4 genome AF: 0.0514 AC: 7826 AN: 152280 Hom.: 306 Cov.: 32 AF XY: 0.0497 AC XY: 3701 AN XY: 74470

African (AFR) AF: 0.0148 AC: 615 AN: 41566

American (AMR) AF: 0.0374 AC: 572 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 423 AN: 3472

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5164

South Asian (SAS) AF: 0.0617 AC: 298 AN: 4826

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10608

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0774 AC: 5265 AN: 68030

Other (OTH) AF: 0.0582 AC: 123 AN: 2112

Alfa AF: 0.0475 Hom.: 94

Bravo AF: 0.0499

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

ClinVar submissions

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	-0.69
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7789679; hg19: chr7-100320221;