rs770402221

Variant names:

• chr1-43352607-CCT-C
• rs770402221
• NM_005373.3:c.1744_1745delCT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_005373.3(MPL):​c.1744_1745delCT​(p.Leu582ValfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MPL NM_005373.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 1-43352607-CCT-C is Pathogenic according to our data. Variant chr1-43352607-CCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458369.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3	c.1744_1745delCT	p.Leu582ValfsTer30	frameshift_variant	Exon 12 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.1744_1745delCT	p.Leu582ValfsTer30	frameshift_variant	Exon 12 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7	c.1723_1724delCT	p.Leu575ValfsTer30	frameshift_variant	Exon 12 of 12	1		ENSP00000414004.3
MPL	ENST00000643351.1	c.400_401delCT	p.Leu134fs	frameshift_variant	Exon 4 of 4			ENSP00000495154.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251472 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461894 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary myelofibrosis;C3275998:Thrombocythemia 2;C5882667:Congenital amegakaryocytic thrombocytopenia 1 Pathogenic:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital amegakaryocytic thrombocytopenia Pathogenic:1

Apr 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MPL c.1744_1745delCT (p.Leu582ValfsX30) results in a premature termination codon, predicted to cause a truncation in the last exon of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not expected to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acids of the protein. Downstream missense variants have been reported in the literature in individuals with congenital amegakaryocytic thrombocytopaenia (PMIDs: 18422784, 11071383, 17666371) and reported as pathogenic in ClinVar, suggesting the disrupted region is clinically significant. Additionally, truncating variants downstream of this position have been reported as pathogenic in ClinVar. The variant allele was found at a frequency of 1.6e-05 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1744_1745delCT in individuals affected with Congenital Amegakaryocytic Thrombocytopenia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu582Valfs*30) in the MPL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the MPL protein. This variant is present in population databases (rs770402221, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 458369). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MPL protein in which other variant(s) (p.Gly614Val) have been observed in individuals with MPL-related conditions (PMID: 17666371). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770402221; hg19: chr1-43818278;