chr7-100722528-C-T

Variant names:

• chr7-100722528-C-T
• rs484199
• NM_000799.4:c.247-136C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000799.4(EPO):​c.247-136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 351,634 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.090 (152 hom., cov: 0)
  • Exomes 𝑓: 0.076 (718 hom.)
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.542
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-100722528-C-T is Benign according to our data. Variant chr7-100722528-C-T is described in ClinVar as Benign. ClinVar VariationId is 1250657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

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.247-136C>T		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.247-136C>T		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes AF: 0.0904 AC: 5554 AN: 61424 Hom.: 154 Cov.: 0

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.273

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.138

GnomAD4 exome AF: 0.0762 AC: 22121 AN: 290200 Hom.: 718 AF XY: 0.0823 AC XY: 12572 AN XY: 152788

African (AFR) AF: 0.0205 AC: 120 AN: 5852

American (AMR) AF: 0.0703 AC: 624 AN: 8878

Ashkenazi Jewish (ASJ) AF: 0.0947 AC: 825 AN: 8714

East Asian (EAS) AF: 0.00430 AC: 72 AN: 16728

South Asian (SAS) AF: 0.160 AC: 4219 AN: 26290

European-Finnish (FIN) AF: 0.0532 AC: 1559 AN: 29320

Middle Eastern (MID) AF: 0.215 AC: 284 AN: 1324

European-Non Finnish (NFE) AF: 0.0747 AC: 13228 AN: 177008

Other (OTH) AF: 0.0740 AC: 1190 AN: 16086

GnomAD4 genome AF: 0.0903 AC: 5548 AN: 61434 Hom.: 152 Cov.: 0 AF XY: 0.0922 AC XY: 2782 AN XY: 30166

African (AFR) AF: 0.0255 AC: 368 AN: 14444

American (AMR) AF: 0.100 AC: 562 AN: 5620

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 210 AN: 1336

East Asian (EAS) AF: 0.0174 AC: 28 AN: 1608

South Asian (SAS) AF: 0.178 AC: 426 AN: 2388

European-Finnish (FIN) AF: 0.0874 AC: 413 AN: 4724

Middle Eastern (MID) AF: 0.246 AC: 29 AN: 118

European-Non Finnish (NFE) AF: 0.111 AC: 3319 AN: 29882

Other (OTH) AF: 0.137 AC: 116 AN: 844

Alfa AF: 0.0964 Hom.: 24

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.093
DANN	Benign	0.15
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs484199; hg19: chr7-100320151; COSMIC: COSV53161341;