7-100722057-CTTTTT-CTTTTTTTTT

Variant names:

• chr7-100722057-C-CTTTT
• rs111249118
• NM_000799.4:c.246+21_246+24dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000799.4(EPO):​c.246+21_246+24dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,241,936 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000024 (0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+21_246+24dupTTTT		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+10insTTTT		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1241936 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 620914

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

African (AFR) AF: 0.00 AC: 0 AN: 27534

American (AMR) AF: 0.00 AC: 0 AN: 28496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21532

East Asian (EAS) AF: 0.00 AC: 0 AN: 36734

South Asian (SAS) AF: 0.00 AC: 0 AN: 71870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4802

European-Non Finnish (NFE) AF: 0.00000314 AC: 3 AN: 954694

Other (OTH) AF: 0.00 AC: 0 AN: 52060

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111249118; hg19: chr7-100319680;