7-100722057-CTTTTT-CTTTT

Variant names:

• chr7-100722057-CT-C
• rs111249118
• NM_000799.4:c.246+24delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000799.4(EPO):​c.246+24delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,216,430 control chromosomes in the GnomAD database, including 120 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (115 hom., cov: 31)
  • Exomes 𝑓: 0.20 (5 hom.)
• Consequence: EPO NM_000799.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.33
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 7-100722057-CT-C is Benign according to our data. Variant chr7-100722057-CT-C is described in ClinVar as Benign. ClinVar VariationId is 1271500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 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.246+24delT		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.246+10delT		intron	N/A	ENSP00000252723.2	P01588

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3511 AN: 140696 Hom.: 115 Cov.: 31

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00364

Gnomad SAS AF: 0.00226

Gnomad FIN AF: 0.00529

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.0222

GnomAD2 exomes AF: 0.333 AC: 36622 AN: 109950 AF XY: 0.337

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.318

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.202 AC: 216800 AN: 1075746 Hom.: 5 Cov.: 0 AF XY: 0.204 AC XY: 108767 AN XY: 534046

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.228 AC: 5594 AN: 24488

American (AMR) AF: 0.230 AC: 5650 AN: 24578

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 4029 AN: 18154

East Asian (EAS) AF: 0.238 AC: 6904 AN: 28958

South Asian (SAS) AF: 0.201 AC: 12196 AN: 60688

European-Finnish (FIN) AF: 0.217 AC: 7830 AN: 36068

Middle Eastern (MID) AF: 0.185 AC: 734 AN: 3964

European-Non Finnish (NFE) AF: 0.197 AC: 164479 AN: 834720

Other (OTH) AF: 0.213 AC: 9384 AN: 44128

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0250 AC: 3518 AN: 140684 Hom.: 115 Cov.: 31 AF XY: 0.0248 AC XY: 1688 AN XY: 68162

African (AFR) AF: 0.0768 AC: 2970 AN: 38674

American (AMR) AF: 0.0169 AC: 234 AN: 13882

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 5 AN: 3304

East Asian (EAS) AF: 0.00345 AC: 17 AN: 4928

South Asian (SAS) AF: 0.00227 AC: 10 AN: 4396

European-Finnish (FIN) AF: 0.00529 AC: 44 AN: 8324

Middle Eastern (MID) AF: 0.0110 AC: 3 AN: 272

European-Non Finnish (NFE) AF: 0.00301 AC: 193 AN: 64112

Other (OTH) AF: 0.0221 AC: 42 AN: 1902

Alfa AF: 0.00659 Hom.: 0

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
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs111249118; hg19: chr7-100319680; COSMIC: COSV53161139;