Genetic Variant EPO:c.246+23_246+24dupTT (chr7-100722057-C-CTT) – ACMG Classification: Uncertain_significance (0 pts)

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+24dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,372,718 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 0.000050 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 0 hom. )

Consequence

EPO
NM_000799.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.33

Publications

0 publications found

Variant links:

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

EPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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+24dupTT		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+10insTT		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes

AF:

0.0000497

AC:

AN:

140904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000103

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:

0.0000467

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00205

AC:

225

AN:

109950

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.00404

Gnomad AMR exome

AF:

0.00253

Gnomad ASJ exome

AF:

0.00312

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.00274

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00188

GnomAD4 exome

AF:

0.00162

AC:

1999

AN:

1231814

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

989

AN XY:

616142

show subpopulations

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

African (AFR)

AF:

0.00355

AC:

AN:

27356

American (AMR)

AF:

0.00155

AC:

AN:

28326

Ashkenazi Jewish (ASJ)

AF:

0.00140

AC:

AN:

21422

East Asian (EAS)

AF:

0.000793

AC:

AN:

36588

South Asian (SAS)

AF:

0.00161

AC:

115

AN:

71466

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

44040

Middle Eastern (MID)

AF:

0.000836

AC:

AN:

4784

European-Non Finnish (NFE)

AF:

0.00166

AC:

1574

AN:

946162

Other (OTH)

AF:

0.00141

AC:

AN:

51670

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.253

Heterozygous variant carriers

265

530

794

1059

1324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000497

AC:

AN:

140904

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

68272

show subpopulations

African (AFR)

AF:

0.000103

AC:

AN:

38654

American (AMR)

AF:

0.00

AC:

AN:

13894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3312

East Asian (EAS)

AF:

0.00

AC:

AN:

4952

South Asian (SAS)

AF:

0.00

AC:

AN:

4430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000467

AC:

AN:

64212

Other (OTH)

AF:

0.00

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000156

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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7-100722057-CTTTTT-CTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over