chr19-11378049-G-A

Position:

• chr19-11378049-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 -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 [Likely_benign]. Clinvar id is 268130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11378049-G-A is described in Lovd as [Likely_pathogenic].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 812 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPOR	NM_000121.4	c.1462C>T	p.Pro488Ser	missense_variant	8/8	ENST00000222139.11	NP_000112.1
EPOR	NR_033663.2	n.1819C>T		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPOR	ENST00000222139.11	c.1462C>T	p.Pro488Ser	missense_variant	8/8	1	NM_000121.4	ENSP00000222139	P1

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

GnomAD3 exomes AF: 0.00768 AC: 1930 AN: 251314 Hom.: 34 AF XY: 0.00657 AC XY: 893 AN XY: 135888

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 SAS exome AF: 0.00317

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

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.0311

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00333

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00445

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

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00359

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00319 Hom.: 4

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

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	EPOR: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -

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

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Intellectual disability-hypotonic facies syndrome, X-linked, 1 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Pro488Ser variant in EPOR has been identified in an individual with polycythaemia (PMID: 8174675), and has been identified in >3% of Latino chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Pro488Ser variant may not impact protein function (PMID: 8174675). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal dominant polycythaemia. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.95	N
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

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: rs142094773; hg19: chr19-11488725;