chr1-43338767-C-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_005373.3(MPL):c.391+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,601,474 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0040 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0018 ( 20 hom. )
Consequence
MPL
NM_005373.3 intron
NM_005373.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.266
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 1-43338767-C-T is Benign according to our data. Variant chr1-43338767-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00176 (2547/1449264) while in subpopulation MID AF= 0.0214 (121/5656). AF 95% confidence interval is 0.0183. There are 20 homozygotes in gnomad4_exome. There are 1253 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 20 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPL | NM_005373.3 | c.391+47C>T | intron_variant | ENST00000372470.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.391+47C>T | intron_variant | 1 | NM_005373.3 | P1 | |||
MPL | ENST00000413998.7 | c.370+47C>T | intron_variant | 1 | |||||
MPL | ENST00000638732.1 | n.391+47C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.00400 AC: 609AN: 152092Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00274 AC: 685AN: 249858Hom.: 2 AF XY: 0.00265 AC XY: 358AN XY: 135138
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GnomAD4 exome AF: 0.00176 AC: 2547AN: 1449264Hom.: 20 Cov.: 29 AF XY: 0.00174 AC XY: 1253AN XY: 721664
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GnomAD4 genome AF: 0.00402 AC: 612AN: 152210Hom.: 1 Cov.: 32 AF XY: 0.00414 AC XY: 308AN XY: 74430
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at