19-11377480-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000121.4(EPOR):c.*504G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00997 in 454,078 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (24 hom., cov: 32)
  • Exomes 𝑓: 0.010 (49 hom.)
• Consequence: EPOR NM_000121.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.433

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-11377480-C-T is Benign according to our data. Variant chr19-11377480-C-T is described in ClinVar as [Benign]. Clinvar id is 328134.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00952 (1449/152236) while in subpopulation AMR AF= 0.0441 (674/15276). AF 95% confidence interval is 0.0414. There are 24 homozygotes in gnomad4. There are 770 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1448 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPOR	NM_000121.4	c.*504G>A		3_prime_UTR_variant	8/8	ENST00000222139.11
EPOR	NR_033663.2	n.2388G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPOR	ENST00000222139.11	c.*504G>A		3_prime_UTR_variant	8/8	1	NM_000121.4	P1

Frequencies

GnomAD3 genomes AF: 0.00952 AC: 1448 AN: 152118 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0136 AC: 1738 AN: 128058 Hom.: 42 AF XY: 0.0108 AC XY: 759 AN XY: 70126

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.000288

Gnomad SAS exome AF: 0.00161

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.00797

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0102 AC: 3079 AN: 301842 Hom.: 49 Cov.: 0 AF XY: 0.00862 AC XY: 1482 AN XY: 172024

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.0488

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.000326

Gnomad4 SAS exome AF: 0.00171

Gnomad4 FIN exome AF: 0.00978

Gnomad4 NFE exome AF: 0.00855

Gnomad4 OTH exome AF: 0.00833

GnomAD4 genome AF: 0.00952 AC: 1449 AN: 152236 Hom.: 24 Cov.: 32 AF XY: 0.0103 AC XY: 770 AN XY: 74434

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0441

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.00789

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00461 Hom.: 1

Bravo AF: 0.0122

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary familial polycythemia due to EPO receptor mutation Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.2
Dann	Benign	0.64

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: rs150535617; hg19: chr19-11488156; COSMIC: COSV105838240; COSMIC: COSV105838240;