19-11378201-C-T

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.1310G>A(p.Arg437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000821 in 1,614,070 control chromosomes in the GnomAD database, including 9 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (5 hom.)
• Consequence: EPOR NM_000121.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.315

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=0.0051923096).
• BP6: Variant 19-11378201-C-T is Benign according to our data. Variant chr19-11378201-C-T is described in ClinVar as [Benign]. Clinvar id is 268129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 374 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPOR	NM_000121.4	c.1310G>A	p.Arg437His	missense_variant	8/8	ENST00000222139.11
EPOR	NR_033663.2	n.1667G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPOR	ENST00000222139.11	c.1310G>A	p.Arg437His	missense_variant	8/8	1	NM_000121.4	P1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152084 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000999 AC: 251 AN: 251288 Hom.: 2 AF XY: 0.000935 AC XY: 127 AN XY: 135852

Gnomad AFR exome AF: 0.00684

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000650 AC: 950 AN: 1461868 Hom.: 5 Cov.: 32 AF XY: 0.000652 AC XY: 474 AN XY: 727238

Gnomad4 AFR exome AF: 0.00600

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000472

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152202 Hom.: 4 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74430

Gnomad4 AFR AF: 0.00696

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000950 Hom.: 0

Bravo AF: 0.00284

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	12
Dann	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.033
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Polyphen		0.0080	B
Vest4		0.049
MVP		0.39
MPC		0.27
ClinPred		0.0038	T
GERP RS		2.8
Varity_R		0.047
gMVP		0.24

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: rs62638744; hg19: chr19-11488877; COSMIC: COSV55801746; COSMIC: COSV55801746;