ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.1654-10T>A (rs200460456)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000390481 SCV000357792 likely benign Thrombocythemia 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000309183 SCV000357793 likely benign Congenital amegakaryocytic thrombocytopenia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000464665 SCV000563307 benign Congenital amegakaryocytic thrombocytopenia; essential thrombocytemia 2020-12-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356726 SCV001551970 likely benign not provided no assertion criteria provided clinical testing 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.

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