chr19-11378051-T-C

Position:

chr19-11378051-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:2

Conservation

PhyloP100: 3.54

Variant links:

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 links:

EPOR (HGNC:):

EPOR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 234) in uniprot entity EPOR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000121.4

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 GnomAd4 at 931 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPOR	NM_000121.4 linkuse as main transcript	c.1460A>G	p.Asn487Ser	missense_variant	8/8	ENST00000222139.11	NP_000112.1	P19235-1
EPOR	NR_033663.2 linkuse as main transcript	n.1817A>G		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPOR	ENST00000222139.11 linkuse as main transcript	c.1460A>G	p.Asn487Ser	missense_variant	8/8	1	NM_000121.4	ENSP00000222139.5		P19235-1

Frequencies

GnomAD3 genomes

AF:

0.00611

AC:

929

AN:

152020

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00602

AC XY:

818

AN XY:

135894

show subpopulations

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.:

Cov.:

AF XY:

0.00654

AC XY:

4755

AN XY:

727236

show subpopulations

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.:

Cov.:

AF XY:

0.00663

AC XY:

493

AN XY:

74388

show subpopulations

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.:

Bravo

AF:

0.00469

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00571

AC:

693

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00575

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	EPOR: BP4, BS2 -

Primary familial polycythemia due to EPO receptor mutation

Benign:1Other: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 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

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

REVEL

Benign

0.036

Sift

Uncertain

0.019

Sift4G

Uncertain

0.033

Polyphen

0.031

Vest4

0.23

MVP

0.54

MPC

0.37

ClinPred

0.026

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over