rs142094773

Variant names:

• chr19-11378049-G-A
• rs142094773
• NM_000121.4:c.1462C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000121.4(EPOR):​c.1462C>T​(p.Pro488Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0048 in 1,614,162 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (56 hom.)
• Consequence: EPOR NM_000121.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.51
• Publications: 19 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075773597).
• BP6: Variant 19-11378049-G-A is Benign according to our data. Variant chr19-11378049-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 268130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00533 (812/152286) while in subpopulation AMR AF = 0.0222 (339/15290). AF 95% confidence interval is 0.0202. There are 15 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 812 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPOR	NM_000121.4	MANE Select	c.1462C>T	p.Pro488Ser	missense	Exon 8 of 8	NP_000112.1
	EPOR	NR_033663.2		n.1819C>T		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPOR	ENST00000222139.11	TSL:1 MANE Select	c.1462C>T	p.Pro488Ser	missense	Exon 8 of 8	ENSP00000222139.5
	EPOR	ENST00000586890.5	TSL:1	n.*1205C>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000467230.1
	EPOR	ENST00000588681.5	TSL:1	n.1847C>T		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 806 AN: 152168 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00768 AC: 1930 AN: 251314 AF XY: 0.00657

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00474 AC: 6929 AN: 1461876 Hom.: 56 Cov.: 32 AF XY: 0.00445 AC XY: 3235 AN XY: 727236

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.0311 AC: 1393 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 108 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00333 AC: 287 AN: 86258

European-Finnish (FIN) AF: 0.0120 AC: 639 AN: 53404

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00378 AC: 4205 AN: 1112010

Other (OTH) AF: 0.00445 AC: 269 AN: 60396

GnomAD4 genome AF: 0.00533 AC: 812 AN: 152286 Hom.: 15 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74456

African (AFR) AF: 0.00118 AC: 49 AN: 41564

American (AMR) AF: 0.0222 AC: 339 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00359 AC: 244 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00372 Hom.: 11

Bravo AF: 0.00545

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00581 AC: 705

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00290

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Primary familial polycythemia due to EPO receptor mutation (3)
-	-	1	Intellectual disability-hypotonic facies syndrome, X-linked, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.12
Sift	Benign	0.36	T
Sift4G	Benign	0.11	T
Polyphen		0.010	B
Vest4		0.083
MVP		0.65
MPC		0.23
ClinPred		0.0076	T
GERP RS		3.8
Varity_R		0.033
gMVP		0.39
Mutation Taster		=93/7	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: rs142094773; hg19: chr19-11488725;