rs886039426

chr1-43338704-CT-Cchr1-43338704-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005373.3(MPL):c.378del(p.Phe126LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: MPL NM_005373.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.99

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-43338704-CT-C is Pathogenic according to our data. Variant chr1-43338704-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 265249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPL	NM_005373.3	c.378del	p.Phe126LeufsTer5	frameshift_variant	3/12	ENST00000372470.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPL	ENST00000372470.9	c.378del	p.Phe126LeufsTer5	frameshift_variant	3/12	1	NM_005373.3	P1
MPL	ENST00000413998.7	c.357del	p.Phe119LeufsTer5	frameshift_variant	3/12	1
MPL	ENST00000638732.1	n.378del		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251458 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135908

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000153 AC: 223 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 727224

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: 0.000197

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2018	Variant summary: MPL c.378delT (p.Phe126LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 277158 control chromosomes. The variant, c.378delT, has been reported in the literature in multiple individuals affected with Congenital Amegakaryocytic Thrombocytopenia (Ballmaier_2001, Germeshausen_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2016	The c.378delT pathogenic variant in the MPL gene has been reported previously in association with congenital amegakaryocytic thrombocytopenia (CAMT) (Ballmaier et al., 2001). The deletion causes a frameshift starting with codon Phenylalanine 126, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Phe126LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change creates a premature translational stop signal (p.Phe126Leufs*5) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs587778515, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 16470591, 28859041). ClinVar contains an entry for this variant (Variation ID: 265249). For these reasons, this variant has been classified as Pathogenic. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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: rs587778515; hg19: chr1-43804375;