chr19-11378222-T-TC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_000121.4(EPOR):​c.1288dupG​(p.Asp430GlyfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Affects (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

EPOR
NM_000121.4 frameshift

Scores

Not classified

Clinical Significance

Affects no assertion criteria provided O:1

Conservation

PhyloP100: 3.30

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • primary familial polycythemia due to EPO receptor mutation
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.157 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPORNM_000121.4 linkc.1288dupG p.Asp430GlyfsTer15 frameshift_variant Exon 8 of 8 ENST00000222139.11 NP_000112.1 P19235-1
EPORNR_033663.2 linkn.1645dupG non_coding_transcript_exon_variant Exon 8 of 8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EPORENST00000222139.11 linkc.1288dupG p.Asp430GlyfsTer15 frameshift_variant Exon 8 of 8 1 NM_000121.4 ENSP00000222139.5 P19235-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Affects
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Primary familial polycythemia due to EPO receptor mutation Other:1
Jul 01, 1995
OMIM
Significance:Affects
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.3
Mutation Taster
=13/187
disease causing

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

Other links and lift over

dbSNP: rs1555716045; hg19: chr19-11488898; API