rs121913616
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM1PM5PP5
The NM_005373.3(MPL):c.1543_1544delinsAA(p.Trp515Lys) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W515L) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
MPL
NM_005373.3 missense
NM_005373.3 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.98
Genes affected
MPL (HGNC:7217): (MPL proto-oncogene, thrombopoietin receptor) In 1990 an oncogene, v-mpl, was identified from the murine myeloproliferative leukemia virus that was capable of immortalizing bone marrow hematopoietic cells from different lineages. In 1992 the human homologue, named, c-mpl, was cloned. Sequence data revealed that c-mpl encoded a protein that was homologous with members of the hematopoietic receptor superfamily. Presence of anti-sense oligodeoxynucleotides of c-mpl inhibited megakaryocyte colony formation. The ligand for c-mpl, thrombopoietin, was cloned in 1994. Thrombopoietin was shown to be the major regulator of megakaryocytopoiesis and platelet formation. The protein encoded by the c-mpl gene, CD110, is a 635 amino acid transmembrane domain, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs . TPO-R deficient mice were severely thrombocytopenic, emphasizing the important role of CD110 and thrombopoietin in megakaryocyte and platelet formation. Upon binding of thrombopoietin CD110 is dimerized and the JAK family of non-receptor tyrosine kinases, as well as the STAT family, the MAPK family, the adaptor protein Shc and the receptors themselves become tyrosine phosphorylated. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PS1
?
Transcript NM_005373.3 (MPL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
In a topological_domain Cytoplasmic (size 121) in uniprot entity TPOR_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_005373.3
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr1-43349338-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14164.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
PP5
?
Variant 1-43349337-TG-AA is Pathogenic according to our data. Variant chr1-43349337-TG-AA is described in ClinVar as [Pathogenic]. Clinvar id is 14165.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPL | NM_005373.3 | c.1543_1544delinsAA | p.Trp515Lys | missense_variant | 10/12 | ENST00000372470.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.1543_1544delinsAA | p.Trp515Lys | missense_variant | 10/12 | 1 | NM_005373.3 | P1 | |
MPL | ENST00000413998.7 | c.1522_1523delinsAA | p.Trp508Lys | missense_variant | 10/12 | 1 | |||
MPL | ENST00000638732.1 | n.1543_1544delinsAA | non_coding_transcript_exon_variant | 10/10 | 1 | ||||
MPL | ENST00000643351.1 | c.75_76delinsAA | p.Trp26Lys | missense_variant | 1/4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Myelofibrosis with myeloid metaplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 15, 2006 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at