chr7-100722667-G-A

Position:

• chr7-100722667-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: EPO NM_000799.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.378

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 -12 ACMG points.

• BP6: Variant 7-100722667-G-A is Benign according to our data. Variant chr7-100722667-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 718151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPO	NM_000799.4	c.250G>A	p.Gly84Arg	missense_variant	4/5	ENST00000252723.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPO	ENST00000252723.3	c.250G>A	p.Gly84Arg	missense_variant	4/5	1	NM_000799.4	P1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152080 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000890 AC XY: 110 AN XY: 123608

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.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 814 AN XY: 715212

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.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74414

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.: 0

Bravo AF: 0.00195

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00297 AC: 13

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.047
Sift	Benign	0.49	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.37		Gain of MoRF binding (P = 0.0159);
MVP		0.69
MPC		1.1
ClinPred		0.019	T
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

Other links and lift over

dbSNP: rs137953994; hg19: chr7-100320290;