rs200460456
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005373.3(MPL):c.1654-10T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,614,024 control chromosomes in the GnomAD database, including 7 homozygotes. 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: 𝑓 0.0019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0021 ( 7 hom. )
Consequence
MPL
NM_005373.3 splice_polypyrimidine_tract, intron
NM_005373.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.008906
2
Clinical Significance
Conservation
PhyloP100: 0.114
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.67).
BP6
?
Variant 1-43352508-T-A is Benign according to our data. Variant chr1-43352508-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr1-43352508-T-A is described in Lovd as [Likely_benign].
BS2
?
High Homozygotes in GnomAdExome4 at 7 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPL | NM_005373.3 | c.1654-10T>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000372470.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.1654-10T>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_005373.3 | P1 | |||
MPL | ENST00000413998.7 | c.1633-10T>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | |||||
MPL | ENST00000643351.1 | c.312-10T>A | splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00185 AC: 282AN: 152022Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00150 AC: 377AN: 251328Hom.: 0 AF XY: 0.00150 AC XY: 204AN XY: 135846
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GnomAD4 exome AF: 0.00208 AC: 3038AN: 1461884Hom.: 7 Cov.: 32 AF XY: 0.00199 AC XY: 1450AN XY: 727240
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GnomAD4 genome ? AF: 0.00185 AC: 282AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Observed in large population cohorts (gnomAD; internal data) - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MPL c.1654-10T>A variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs200460456), ClinVar (reported likely benign by Illumina and benign by Invitae for Congenital amegakaryocytic thrombocytopenia and Essential thrombocythemia), Clinvitae and LOVD 3.0. The variant was identified in control databases in 461 of 282670 chromosomes at a frequency of 0.001631 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 378 of 129002 chromosomes (freq: 0.00293), European (Finnish) in 58 of 25116 chromosomes (freq: 0.002309), Other in 8 of 7226 chromosomes (freq: 0.001107), African in 8 of 24956 chromosomes (freq: 0.000321), Latino in 7 of 35438 chromosomes (freq: 0.000198), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), while the variant was not observed in the East Asian population. The c.1654-10T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Further, 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2022 | Variant summary: MPL c.1654-10T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 251328 control chromosomes, predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1 fold of the estimated maximal predicted 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 Non-Finnish European origin. To our knowledge, no occurrence of c.1654-10T>A in individuals affected with Congenital Amegakaryocytic Thrombocytopenia and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely benign/benign (n=3). Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 02, 2017 | - - |
Congenital amegakaryocytic thrombocytopenia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Thrombocythemia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -29
Find out detailed SpliceAI scores and Pangolin per-transcript scores at