rs200460456
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 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
Consequence
NM_005373.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MPL | ENST00000372470.9 | c.1654-10T>A | intron_variant | Intron 11 of 11 | 1 | NM_005373.3 | ENSP00000361548.3 | |||
MPL | ENST00000413998.7 | c.1633-10T>A | intron_variant | Intron 11 of 11 | 1 | ENSP00000414004.3 | ||||
MPL | ENST00000643351.1 | c.310-10T>A | intron_variant | Intron 3 of 3 | ENSP00000495154.1 |
Frequencies
GnomAD3 genomes AF: 0.00185 AC: 282AN: 152022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00150 AC: 377AN: 251328Hom.: 0 AF XY: 0.00150 AC XY: 204AN XY: 135846
GnomAD4 exome AF: 0.00208 AC: 3038AN: 1461884Hom.: 7 Cov.: 32 AF XY: 0.00199 AC XY: 1450AN XY: 727240
GnomAD4 genome AF: 0.00185 AC: 282AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.00196 AC XY: 146AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
MPL: BS1 -
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Has not been previously published as pathogenic or benign to our knowledge; Observed in large population cohorts (gnomAD; internal data) -
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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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not specified Benign:2
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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. -
Congenital amegakaryocytic thrombocytopenia Benign:1
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Thrombocythemia 1 Benign:1
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Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at