rs141311765
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_005373.3(MPL):āc.754T>Cā(p.Tyr252His) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0011 ( 0 hom., cov: 32)
Exomes š: 0.00011 ( 0 hom. )
Consequence
MPL
NM_005373.3 missense
NM_005373.3 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 4.39
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_benign. Variant got -3 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005373.3
BP4
?
Computational evidence support a benign effect (MetaRNN=0.029650927).
BP6
?
Variant 1-43340027-T-C is Benign according to our data. Variant chr1-43340027-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134834.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, not_provided=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPL | NM_005373.3 | c.754T>C | p.Tyr252His | missense_variant | 5/12 | ENST00000372470.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.754T>C | p.Tyr252His | missense_variant | 5/12 | 1 | NM_005373.3 | P1 | |
MPL | ENST00000413998.7 | c.733T>C | p.Tyr245His | missense_variant | 5/12 | 1 | |||
MPL | ENST00000638732.1 | n.754T>C | non_coding_transcript_exon_variant | 5/10 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00111 AC: 169AN: 152236Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000335 AC: 84AN: 250424Hom.: 0 AF XY: 0.000192 AC XY: 26AN XY: 135468
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GnomAD4 exome AF: 0.000105 AC: 154AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66AN XY: 727244
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GnomAD4 genome ? AF: 0.00110 AC: 168AN: 152354Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85AN XY: 74502
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2023 | Variant summary: MPL c.754T>C (p.Tyr252His) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 250424 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MPL causing Congenital Amegakaryocytic Thrombocytopenia phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.754T>C has been reported in the literature as a VUS in settings of multigene panel testing among cohorts of individuals with Inherited bone marrow failure syndromes (IBMFSs) who remained as "unclassified" based on the reported findings (example, Galvez_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Amegakaryocytic Thrombocytopenia or MPL-related Inherited bone marrow failure syndromes (IBMFSs). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 22, 2021 | This sequence change does not appear to have been previously described in patients with MPL-related disorders and has been described in the gnomAD database with a high population frequency of 0.43% in the African subpopulation (dbSNP rs141311765). The p.Tyr252His change affects a highly conserved amino acid residue located in a domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Tyr252His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Tyr252His change remains unknown at this time. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Congenital amegakaryocytic thrombocytopenia Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The MPL c.754T>C (p.Tyr252His) missense variant has been reported in one study in which it was identified in a heterozygous state in a child with essential thrombocythemia (Lambert et al. 2012). The patient also carried two other variants in the MPL gene in a heterozygous state, one of which was a known polymorphism and the other was found deep in an intron and thought unlikely to be responsible for the phenotype. The variant has not been reported in individuals with congenital amegakaryocytic thrombocytopenia. Control data are unavailable for the p.Tyr252His variant which is reported at a frequency of 0.0052 in the African American population of the Exome Sequencing Project. The Tyr252 residue is noted to be conserved. Wild type and variant MPL were introduced into cytokine-dependent BaF3 cells through retroviral transduction. Cells stably expressing the p.Tyr252His variant allele exhibited increased proliferation in response to thrombopoietin (TPO), in particular at low concentration, when compared to wild type. Upon cytokine withdrawal, cells expressing the variant survived better than those expressing a wild type allele. These data suggest that the p.Tyr252His variant results in increased TPO/MPL-mediated cell growth and may contribute to the development of essential thrombocythemia in vivo (Lambert et al. 2012). In a genome wide association study of nearly 15,000 African Americans, the p.Tyr252His variant was significantly associated with higher platelet counts (Auer et al. 2012). Based on the limited evidence, the p.Tyr152His variant is classified as a variant of unknown significance for essential thrombocythemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Benign
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at