7-100722667-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000799.4(EPO):c.250G>A(p.Gly84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,589,690 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

EPO
NM_000799.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.378

Publications

6 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 7-100722667-G-A is Benign according to our data. Variant chr7-100722667-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 718151.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,Unknown,AR gene

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.250G>A	p.Gly84Arg	missense	Exon 4 of 5	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.250G>A	p.Gly84Arg	missense	Exon 4 of 5	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000996

AC:

225

AN:

225868

AF XY:

0.000890

show subpopulations

Gnomad AFR exome

AF:

0.00300

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00311

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000862

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00114

AC:

1637

AN:

1437494

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

814

AN XY:

715212

show subpopulations

African (AFR)

AF:

0.00371

AC:

118

AN:

31848

American (AMR)

AF:

0.00186

AC:

AN:

37584

Ashkenazi Jewish (ASJ)

AF:

0.00219

AC:

AN:

24648

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.000278

AC:

AN:

82872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52750

Middle Eastern (MID)

AF:

0.00523

AC:

AN:

4210

European-Non Finnish (NFE)

AF:

0.00115

AC:

1268

AN:

1104904

Other (OTH)

AF:

0.00139

AC:

AN:

59118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00160

AC:

244

AN:

152196

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00332

AC:

138

AN:

41546

American (AMR)

AF:

0.00177

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5148

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000956

AC:

AN:

68004

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00133

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00297

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.31

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.53

M_CAP

Benign

0.012

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

PhyloP100

-0.38

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

REVEL

Benign

0.047

Sift

Benign

0.49

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.16

MutPred

0.37

Gain of MoRF binding (P = 0.0159)

MVP

0.69

MPC

1.1

ClinPred

0.019

GERP RS

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: 2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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