NM_000799.4:c.246+24dupT

Variant names:

• chr7-100722057-C-CT
• rs111249118
• NM_000799.4:c.246+24dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000799.4(EPO):​c.246+24dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,297,310 control chromosomes in the GnomAD database, including 80 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (79 hom., cov: 31)
  • Exomes 𝑓: 0.15 (1 hom.)
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0611 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.246+24dupT		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.246+9_246+10insT		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3345 AN: 140772 Hom.: 79 Cov.: 31

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00283

Gnomad SAS AF: 0.00564

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00820

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.113 AC: 12411 AN: 109950 AF XY: 0.110

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.0754

Gnomad NFE exome AF: 0.0978

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.150 AC: 173111 AN: 1156550 Hom.: 1 Cov.: 0 AF XY: 0.147 AC XY: 85112 AN XY: 577582

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.168 AC: 4390 AN: 26192

American (AMR) AF: 0.116 AC: 3111 AN: 26840

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 2602 AN: 20040

East Asian (EAS) AF: 0.117 AC: 3931 AN: 33564

South Asian (SAS) AF: 0.146 AC: 9705 AN: 66372

European-Finnish (FIN) AF: 0.0997 AC: 4068 AN: 40794

Middle Eastern (MID) AF: 0.109 AC: 497 AN: 4550

European-Non Finnish (NFE) AF: 0.155 AC: 137811 AN: 889924

Other (OTH) AF: 0.145 AC: 6996 AN: 48274

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0238 AC: 3350 AN: 140760 Hom.: 79 Cov.: 31 AF XY: 0.0227 AC XY: 1552 AN XY: 68224

African (AFR) AF: 0.0632 AC: 2444 AN: 38690

American (AMR) AF: 0.0125 AC: 174 AN: 13898

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 21 AN: 3310

East Asian (EAS) AF: 0.00284 AC: 14 AN: 4936

South Asian (SAS) AF: 0.00568 AC: 25 AN: 4402

European-Finnish (FIN) AF: 0.0138 AC: 115 AN: 8342

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.00820 AC: 526 AN: 64114

Other (OTH) AF: 0.0157 AC: 30 AN: 1906

Alfa AF: 0.00218 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs111249118; hg19: chr7-100319680;