1-43338634-G-C

Position:

chr1-43338634-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5PP5_Very_Strong

The ENST00000372470.9(MPL):c.305G>C(p.Arg102Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000455 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

MPL
ENST00000372470.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 5.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-43338633-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 644406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 1-43338634-G-C is Pathogenic according to our data. Variant chr1-43338634-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43338634-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPL	NM_005373.3 linkuse as main transcript	c.305G>C	p.Arg102Pro	missense_variant	3/12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9 linkuse as main transcript	c.305G>C	p.Arg102Pro	missense_variant	3/12	1	NM_005373.3	ENSP00000361548	P1	P40238-1
MPL	ENST00000413998.7 linkuse as main transcript	c.284G>C	p.Arg95Pro	missense_variant	3/12	1		ENSP00000414004
MPL	ENST00000638732.1 linkuse as main transcript	n.305G>C		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152126

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000382

AC:

AN:

251490

Hom.:

AF XY:

0.000390

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000475

AC:

694

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000469

AC XY:

341

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.000589

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000263

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000380

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MPL: PM3:Very Strong, PM2, PM5, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 05, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2024	Observed with a second MPL variant in additional patients with congenital amegakaryocytic thrombocytopenia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 19302922, 32581362, 10971406); Identified in the heterozygous state in members of a single family with mild thrombocytosis and/or elevated thrombopoietin levels (PMID: 28979237); Published functional studies demonstrate a damaging effect due to impaired subcellular distribution, impaired glycosylation, and lack of JAK/STAT pathway activation (PMID: 25538044); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 23351976, 27418648, 28034873, 32703794, 18422784, 16470591, 11133753, 15374889, 20188141, 26854587, 26556299, 28955303, 30431218, 30523342, 31589614, 37939832, 35776903, 32191290, 35150448, 34308104, 28859041, 24119002, 31064749, 32581362, 10971406, 19302922, 38752375, 37647632, 25538044, 28979237) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2021	This sequence has been previously described in multiple patients with congenital amegakaryocytic thrombocytopenia (CAMT) in both homozygous and compound heterozygous states with other pathogenic variants in the same gene (PMIDs: 11972523, 28859041, 16470591, 18240171, 19302922, 21225925, 24119002, 26854587). Functional studies have shown that this sequence change impairs trafficking and glycosylation of the receptor expressed at the cell surface (PMIDs: 19302922, 24438083, 25538044). This sequence change has been described in the gnomAD database with a population frequency of 0.071% in non-Finnish Europeans; however, it has not been observed in homozygous state in any individuals (dbSNP rs28928907). The p.Arg102Pro change affects a highly conserved amino acid residue located in the extracellular domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg102Pro substitution. These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 12, 2024	PM1, PM3_strong, PM5, PS3, PS4 -

Congenital amegakaryocytic thrombocytopenia 1

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with recessive congenital amegakaryocytic thrombocytopenia (CAMT) (MIM#604498) and dominant thrombocythemia 2 (MIM#601977), respectively (PMIDs: 28955303, 26423830). (I) 0108 - This gene is associated with autosomal dominant and recessive disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (107 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ligand binding domain (PDB, NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg102Cys) variant has been reported in multiple times, once as pathogenic in a patient with congenital amegakaryocytic thrombocytopenia (CAMT) (ClinVar) and several times in homozygous individuals with CAMT (PMIDs: 25539746, 21659346). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and observed in multiple individuals with autosomal recessive CAMT (ClinVar, PMIDs: 26854587, 21225925, 11972523). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies using transfected human cells showed MPL protein localisation and phosphorylation of signaling proteins were impaired (PMIDs: 28034873, 18422784). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 22, 2024	- -

Congenital amegakaryocytic thrombocytopenia

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2017	Variant summary: The MPL c.305G>C (p.Arg102Pro) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 56/121606 control chromosomes at a frequency of 0.0004605, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). The variant was reported in numerous CAMPT patients in the literature, both in the homozygous and compound heterozygous state. Functional studies have shown the variant to lead to abnormal subcellular receptor distribution, lack of membrane localization, impaired glycosylation as well as impaired TPO signal transduction (Stockklausner_2015, Tijssen_2008). Taken together, this variant is classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 31, 2022

- -

Thrombocytopenia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 102 of the MPL protein (p.Arg102Pro). This variant is present in population databases (rs28928907, gnomAD 0.07%). This missense change has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (CAMT) (PMID: 971406, 11972523, 16470591, 18240171, 19302922, 21225925, 24119002, 26854587, 28859041). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPL protein function. Experimental studies have shown that this missense change affects MPL function (PMID: 18422784, 19302922, 24438083, 25538044). This variant disrupts the p.Arg102 amino acid residue in MPL. Other variant(s) that disrupt this residue have been observed in individuals with MPL-related conditions (PMID: 16470591, 21659346), which suggests that this may be a clinically significant amino acid residue. 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

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.99

A;A

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.52

Sift

Benign

0.082

T;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.93

MVP

0.87

MPC

0.90

ClinPred

0.69

GERP RS

5.6

Varity_R

0.62

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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