NM_000799.4:c.250G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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. 13/23 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 id is 718151.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPO	NM_000799.4 link	c.250G>A	p.Gly84Arg	missense_variant	Exon 4 of 5	ENST00000252723.3	NP_000790.2	P01588G9JKG7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPO	ENST00000252723.3 link	c.250G>A	p.Gly84Arg	missense_variant	Exon 4 of 5	1	NM_000799.4	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

GnomAD3 exomes

AF:

0.000996

AC:

225

AN:

225868

Hom.:

AF XY:

0.000890

AC XY:

110

AN XY:

123608

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 SAS exome

AF:

0.000148

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

Gnomad4 AFR exome

AF:

0.00371

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.00219

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152196

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00332

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00113

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 06, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS4_supporting, BP4, BP5, PM2_moderate -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over