7-100722057-CTTTT-CT

Variant names:

• chr7-100722057-CTTT-C
• rs111249118
• NM_000799.4:c.246+22_246+24delTTT

Variant summary

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

The NM_000799.4(EPO):​c.246+22_246+24delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,234,424 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: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• 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: 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: 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+22_246+24delTTT		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+12delTTT		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 140906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00177 AC: 195 AN: 109950 AF XY: 0.00176

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00205

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000507 AC: 626 AN: 1234424 Hom.: 0 AF XY: 0.000501 AC XY: 309 AN XY: 617084

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

African (AFR) AF: 0.000730 AC: 20 AN: 27408

American (AMR) AF: 0.00103 AC: 29 AN: 28286

Ashkenazi Jewish (ASJ) AF: 0.000936 AC: 20 AN: 21376

East Asian (EAS) AF: 0.000438 AC: 16 AN: 36492

South Asian (SAS) AF: 0.000673 AC: 48 AN: 71374

European-Finnish (FIN) AF: 0.000638 AC: 28 AN: 43866

Middle Eastern (MID) AF: 0.000418 AC: 2 AN: 4784

European-Non Finnish (NFE) AF: 0.000472 AC: 448 AN: 949050

Other (OTH) AF: 0.000290 AC: 15 AN: 51788

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 140906 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68272

African (AFR) AF: 0.00 AC: 0 AN: 38654

American (AMR) AF: 0.00 AC: 0 AN: 13894

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4952

South Asian (SAS) AF: 0.00 AC: 0 AN: 4430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64214

Other (OTH) AF: 0.00 AC: 0 AN: 1902

Alfa AF: 0.000415 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
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; COSMIC: COSV53161267;