rs587778514

Positions:

chr1-43338563-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_005373.3(MPL):c.235_236delCT(p.Leu79fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L79L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MPL
NM_005373.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 2.74

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 links:

MPL (HGNC:):

MPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 1-43338563-CCT-C is Pathogenic according to our data. Variant chr1-43338563-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 134822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPL	NM_005373.3 linkuse as main transcript	c.235_236delCT	p.Leu79fs	frameshift_variant	3/12	ENST00000372470.9	NP_005364.1	P40238-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MPL	ENST00000372470.9 linkuse as main transcript	c.235_236delCT	p.Leu79fs	frameshift_variant	3/12	1	NM_005373.3	ENSP00000361548.3	P40238-1
MPL	ENST00000413998.7 linkuse as main transcript	c.214_215delCT	p.Leu72fs	frameshift_variant	3/12	1		ENSP00000414004.3	Q5JUY5
MPL	ENST00000638732.1 linkuse as main transcript	n.235_236delCT		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251394

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461892

Hom.:

AF XY:

0.0000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2017	Variant summary: The MPL c.235_236delCT (p.Leu79Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent MPL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/121376 control chromosomes at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). The variant has been reported in affected individuals in the literature in the homozygous and compound heterozygous state. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The MPL c.235_236del (p.Leu79GlufsTer84) variant has been reported in homozygous state in individuals affected with Amegakaryocytic Thrombocytopenia, Congenital (Ballmaier M et al.). Experimental studies have shown that this frameshift predicted to result in a complete absence of functional c-Mpl protein. This variant has also been reported to lead to a complete loss of a functional TPO receptor c-Mpl (Ballmaier M et al.). This variant has been submitted with the allele frequency 0.005% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. This variant causes a frameshift starting with codon Leucine 79, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 84 of the new reading frame, denoted p.Leu79GlufsTer84. Loss-of-function variants in MPL are known to be pathogenic (Gurney AL et al.) For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary myelofibrosis;C1327915:Congenital amegakaryocytic thrombocytopenia;C3275998:Thrombocythemia 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 02, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect of no protein expression (Gandhi et al., 2005); This variant is associated with the following publications: (PMID: 19388932, 17666371, 21228398, 16470591, 19302922, 31350202, 29625052, 34426522, 31589614, 11133753, 16219544) -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change creates a premature translational stop signal (p.Leu79Glufs*84) 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 (rs587778514, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 11133753, 17666371). This variant is also known as del235/236. ClinVar contains an entry for this variant (Variation ID: 134822). 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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over