19-11378051-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000121.4(EPOR):c.1460A>G(p.Asn487Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 1,614,018 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (45 hom.)
• Consequence: EPOR NM_000121.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038110912).
• BP6: Variant 19-11378051-T-C is Benign according to our data. Variant chr19-11378051-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 16598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11378051-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 929 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPOR	NM_000121.4	c.1460A>G	p.Asn487Ser	missense_variant	8/8	ENST00000222139.11
EPOR	NR_033663.2	n.1817A>G		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPOR	ENST00000222139.11	c.1460A>G	p.Asn487Ser	missense_variant	8/8	1	NM_000121.4	P1

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 929 AN: 152020 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00626 AC: 1572 AN: 251316 Hom.: 6 AF XY: 0.00602 AC XY: 818 AN XY: 135894

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00670 AC: 9798 AN: 1461880 Hom.: 45 Cov.: 32 AF XY: 0.00654 AC XY: 4755 AN XY: 727236

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00751

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.00703

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00612 AC: 931 AN: 152138 Hom.: 8 Cov.: 32 AF XY: 0.00663 AC XY: 493 AN XY: 74388

Gnomad4 AFR AF: 0.00174

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.00699

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00539 Hom.: 2

Bravo AF: 0.00469

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00571 AC: 693

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary familial polycythemia due to EPO receptor mutation Benign:1 Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
Affects, no assertion criteria provided	literature only	OMIM	Feb 15, 1996	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	EPOR: BP4, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.62	A
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.036
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.033	D
Polyphen		0.031	B
Vest4		0.23
MVP		0.54
MPC		0.37
ClinPred		0.026	T
GERP RS		4.5
Varity_R		0.095
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs62638745; hg19: chr19-11488727; COSMIC: COSV55801754; COSMIC: COSV55801754;