rs148434485

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_005373.3(MPL):c.127C>T(p.Arg43*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MPL
NM_005373.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.90

Publications

9 publications found

Variant links:

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]

MPL Gene-Disease associations (from GenCC):

thrombocythemia 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
congenital amegakaryocytic thrombocytopenia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
congenital amegakaryocytic thrombocytopenia 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
familial thrombocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary isolated aplastic anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-43338146-C-T is Pathogenic according to our data. Variant chr1-43338146-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 371574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3 link	c.127C>T	p.Arg43*	stop_gained	Exon 2 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MPL	ENST00000372470.9 link	c.127C>T	p.Arg43*	stop_gained	Exon 2 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7 link	c.106C>T	p.Arg36*	stop_gained	Exon 2 of 12	1		ENSP00000414004.3
MPL	ENST00000638732.1 link	n.127C>T		non_coding_transcript_exon_variant	Exon 2 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251424

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000334

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MPL-related disorder

Pathogenic:2

Apr 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MPL c.127C>T variant is predicted to result in premature protein termination (p.Arg43*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with congenital amegakaryocytic thrombocytopenia (Table 4, Ballmaier et al. 2001. PubMed ID: 11133753; Table 1, Germeshausen et al. 2006. PubMed ID: 16470591; Savoia et al. 2007. PubMed ID: 17666371). This variant has also been observed in the heterozygous state in an individual with lung adenocarcinoma (Table S2, Huang et al. 2018. PubMed ID: 29625052). This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD. Nonsense variants in MPL are expected to be pathogenic. This variant is interpreted as pathogenic. -

Oct 04, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MPL c.127C>T (p.Arg43Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in three studies in which it is identified in a total of six individuals with congenital amegakaryocytic thrombocytopenia, all with a severe phenotype, in one individual in a compound heterozygous state and in five individuals in a homozygous state (Ballmaier et al. 2001; Germeshausen et al. 2006; Savoia et al. 2007). The p.Arg43Ter variant has not been reported in individuals with essential thrombocythemia. The p.Arg43Ter variant was absent from 50 controls and is reported at a frequency of 0.000041 in the total population of the Exome Aggregation Consortium. Savoia et al. (2007) demonstrated that platelet surface expression of other glycoproteins was normal in one individual carrying the variant but MPL expression was scarcely detectable. Serum TPO levels were elevated and in colony-forming unit assays, platelet c-MPL and bone marrow colonies were reduced. Based on the evidence and potential impact of stop-gained variants, the p.Arg43Ter variant is classified as pathogenic for MPL-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Congenital amegakaryocytic thrombocytopenia 1

Pathogenic:2

Oct 31, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1+PM3 -

Congenital amegakaryocytic thrombocytopenia

Pathogenic:2

Aug 25, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 25, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MPL c.127C>T (p.Arg43X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 251424 control chromosomes. c.127C>T has been reported in the literature in multiple individuals affected with Congenital Amegakaryocytic Thrombocytopenia (example, Ballmaier_2001, Germeshausen_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MPL: PVS1, PM2, PM3 -

Sep 02, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Pathogenic:1

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg43*) 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 (rs148434485, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 16470591). ClinVar contains an entry for this variant (Variation ID: 371574). For these reasons, this variant has been classified as Pathogenic. -

Thrombocythemia 2

Pathogenic:1

May 12, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MPL c.127C>T (p.Arg43Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). Colony assays have shown a notable decrease in the total number of colony-forming cells from congenital amegakaryocytic thrombocytopenia I patients carrying this variant and other nonsense mutations compared to those from healthy donors (PMID: 16470591). In addition, an expression analysis conducted on hematopoietic progenitor cells revealed a lack of CD110 expression in patients harboring this variant, as well as in individuals with other nonsense or frameshift mutations and mutations predicted to result in complete splice site loss (PMID: 32703794). This variant has been identified as a homozygous mutation in multiple individuals with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 16470591, 17666371, 18090929). To our knowledge, this variant has not been reported in individuals with thrombocythemia. This variant has a maximum subpopulation frequency of 0.018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.78

PhyloP100

1.9

Vest4

0.90

GERP RS

4.8

PromoterAI

-0.00070

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over