rs138190746

Variant names:

• chr19-11378113-A-G
• rs138190746
• NM_000121.4:c.1398T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000121.4(EPOR):​c.1398T>C​(p.Thr466Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,614,106 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: EPOR NM_000121.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.225
• Publications: 1 publications found

Genes affected

EPOR (HGNC:3416): (erythropoietin receptor) This gene encodes the erythropoietin receptor which is a member of the cytokine receptor family. Upon erythropoietin binding, this receptor activates Jak2 tyrosine kinase which activates different intracellular pathways including: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. The stimulated erythropoietin receptor appears to have a role in erythroid cell survival. Defects in the erythropoietin receptor may produce erythroleukemia and familial erythrocytosis. Dysregulation of this gene may affect the growth of certain tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

EPOR Gene-Disease associations (from GenCC):

• primary familial polycythemia due to EPO receptor mutation

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-11378113-A-G is Benign according to our data. Variant chr19-11378113-A-G is described in ClinVar as Benign. ClinVar VariationId is 328141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.225 with no splicing effect.
• BS2: High AC in GnomAd4 at 176 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000121.4. 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
	EPOR	NM_000121.4	MANE Select	c.1398T>C	p.Thr466Thr	synonymous	Exon 8 of 8	NP_000112.1	P19235-1
	EPOR	NR_033663.2		n.1755T>C		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPOR	ENST00000222139.11	TSL:1 MANE Select	c.1398T>C	p.Thr466Thr	synonymous	Exon 8 of 8	ENSP00000222139.5	P19235-1
	EPOR	ENST00000586890.5	TSL:1	n.*1141T>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000467230.1	K7EP50
	EPOR	ENST00000588681.5	TSL:1	n.1783T>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000856 AC: 215 AN: 251296 AF XY: 0.000751

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000514 AC: 752 AN: 1461844 Hom.: 6 Cov.: 32 AF XY: 0.000495 AC XY: 360 AN XY: 727228

African (AFR) AF: 0.00382 AC: 128 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 286 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000202 AC: 225 AN: 1112012

Other (OTH) AF: 0.00123 AC: 74 AN: 60396

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74460

African (AFR) AF: 0.00250 AC: 104 AN: 41550

American (AMR) AF: 0.000915 AC: 14 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00160 Hom.: 2

Bravo AF: 0.00146

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary familial polycythemia due to EPO receptor mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.3
DANN	Benign	0.77
PhyloP100		-0.23
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: rs138190746; hg19: chr19-11488789;