7-100722010-G-A

Position:

• chr7-100722010-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000799.4(EPO):​c.208G>A​(p.Asp70Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00396 in 1,612,388 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (15 hom.)
• Consequence: EPO NM_000799.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.80

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016564637).
• BP6: Variant 7-100722010-G-A is Benign according to our data. Variant chr7-100722010-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 715578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPO	NM_000799.4	c.208G>A	p.Asp70Asn	missense_variant	3/5	ENST00000252723.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPO	ENST00000252723.3	c.208G>A	p.Asp70Asn	missense_variant	3/5	1	NM_000799.4	P1

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 405 AN: 151920 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00243 AC: 608 AN: 250106 Hom.: 0 AF XY: 0.00234 AC XY: 316 AN XY: 135210

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000936

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000562

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00410 AC: 5986 AN: 1460380 Hom.: 15 Cov.: 32 AF XY: 0.00395 AC XY: 2872 AN XY: 726492

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.000992

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000594

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00266 AC: 404 AN: 152008 Hom.: 1 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74280

Gnomad4 AFR AF: 0.000868

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000952

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00403 Hom.: 2

Bravo AF: 0.00272

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00350

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	EPO: BS1 -

EPO-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.57	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Benign	0.054	T
Sift4G	Benign	0.19	T
Polyphen		0.92	P
Vest4		0.57
MVP		0.77
MPC		1.0
ClinPred		0.052	T
GERP RS		4.4
Varity_R		0.43
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs62483572; hg19: chr7-100319633;