Submissions for variant NM_005373.3(MPL):c.1654-10T>A

gnomAD frequency: 0.00196  dbSNP: rs200460456

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000390481	SCV000357792	likely benign	Thrombocythemia 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000309183	SCV000357793	likely benign	Congenital amegakaryocytic thrombocytopenia	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464665	SCV000563307	benign	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2025-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001356726	SCV001811351	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Observed in large population cohorts (gnomAD; internal data)
Genetic Services Laboratory, University of Chicago	RCV001820856	SCV002065641	likely benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001820856	SCV002766286	benign	not specified	2022-11-21	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001356726	SCV005878429	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001356726	SCV005890039	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	MPL: BS1
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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001356726	SCV002036750	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001356726	SCV002037798	likely benign	not provided		no assertion criteria provided	clinical testing