rs121913616

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM1PM2PM5PP5

The ENST00000372470.9(MPL):​c.1543_1544delinsAA​(p.Trp515Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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
ENST00000372470.9 missense

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.98
Variant links:
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 9 ACMG points.

PS1
Transcript ENST00000372470.9 (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 ENST00000372470.9
PM2
Very rare variant in population databases, with high coverage;
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 Protein UniProt
MPLNM_005373.3 linkuse as main transcriptc.1543_1544delinsAA p.Trp515Lys missense_variant 10/12 ENST00000372470.9 NP_005364.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MPLENST00000372470.9 linkuse as main transcriptc.1543_1544delinsAA p.Trp515Lys missense_variant 10/121 NM_005373.3 ENSP00000361548 P1P40238-1
MPLENST00000413998.7 linkuse as main transcriptc.1522_1523delinsAA p.Trp508Lys missense_variant 10/121 ENSP00000414004
MPLENST00000638732.1 linkuse as main transcriptn.1543_1544delinsAA non_coding_transcript_exon_variant 10/101
MPLENST00000643351.1 linkuse as main transcriptc.75_76delinsAA p.Trp26Lys missense_variant 1/4 ENSP00000495154

Frequencies

GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
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 providedliterature onlyOMIMNov 15, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913616; hg19: chr1-43815008; COSMIC: COSV65243979; API