7-100722057-CTTTTT-CTTT

Variant names:

• chr7-100722057-CTT-C
• rs111249118
• NM_000799.4:c.246+23_246+24delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000799.4(EPO):​c.246+23_246+24delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,335,650 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000099 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0067 (1 hom.)
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.928
• 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: Uncertain_significance. The variant received 0 ACMG points.

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+23_246+24delTT		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+10_246+11delTT		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes AF: 0.0000923 AC: 13 AN: 140870 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00135

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.000526

GnomAD2 exomes AF: 0.0173 AC: 1899 AN: 109950 AF XY: 0.0170

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.0159

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.00666 AC: 7954 AN: 1194790 Hom.: 1 AF XY: 0.00673 AC XY: 4020 AN XY: 597080

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

African (AFR) AF: 0.00709 AC: 189 AN: 26676

American (AMR) AF: 0.0104 AC: 282 AN: 27194

Ashkenazi Jewish (ASJ) AF: 0.00825 AC: 170 AN: 20616

East Asian (EAS) AF: 0.00657 AC: 230 AN: 35034

South Asian (SAS) AF: 0.00817 AC: 564 AN: 68994

European-Finnish (FIN) AF: 0.00694 AC: 293 AN: 42216

Middle Eastern (MID) AF: 0.00386 AC: 18 AN: 4668

European-Non Finnish (NFE) AF: 0.00638 AC: 5866 AN: 919306

Other (OTH) AF: 0.00683 AC: 342 AN: 50086

⚠️ 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: 0.0000994 AC: 14 AN: 140860 Hom.: 1 Cov.: 31 AF XY: 0.000176 AC XY: 12 AN XY: 68272

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

African (AFR) AF: 0.000103 AC: 4 AN: 38702

American (AMR) AF: 0.000144 AC: 2 AN: 13908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3312

East Asian (EAS) AF: 0.00 AC: 0 AN: 4936

South Asian (SAS) AF: 0.00114 AC: 5 AN: 4402

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 64188

Other (OTH) AF: 0.000524 AC: 1 AN: 1908

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00311541), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00114 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93
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;