rs41269541

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000638732.1(MPL):n.1570C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,611,486 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 44 hom. )

Consequence

MPL
ENST00000638732.1 non_coding_transcript_exon

Scores

Splicing: ADA: 0.00001505

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11O:1

Conservation

PhyloP100: 0.644

Publications

12 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: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.109).

BP6

Variant 1-43349364-C-T is Benign according to our data. Variant chr1-43349364-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00754 (11008/1459190) while in subpopulation NFE AF = 0.00895 (9947/1111554). AF 95% confidence interval is 0.0088. There are 44 homozygotes in GnomAdExome4. There are 5235 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3 link	c.1565+5C>T		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000372470.9	NP_005364.1	P40238-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MPL	ENST00000638732.1 link	n.1570C>T	non_coding_transcript_exon_variant	Exon 10 of 10	1
MPL	ENST00000372470.9 link	c.1565+5C>T	splice_region_variant, intron_variant	Intron 10 of 11	1	NM_005373.3	ENSP00000361548.3	P40238-1
MPL	ENST00000413998.7 link	c.1544+5C>T	splice_region_variant, intron_variant	Intron 10 of 11	1		ENSP00000414004.3	Q5JUY5
MPL	ENST00000643351.1 link	c.95+5C>T	splice_region_variant, intron_variant	Intron 1 of 3			ENSP00000495154.1	A0A2R8YE13

Frequencies

GnomAD3 genomes

AF:

0.00476

AC:

724

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00828

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00451

AC:

1119

AN:

248126

AF XY:

0.00442

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.000499

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.00725

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00754

AC:

11008

AN:

1459190

Hom.:

Cov.:

AF XY:

0.00721

AC XY:

5235

AN XY:

726006

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33474

American (AMR)

AF:

0.00190

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.000881

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00109

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00699

AC:

359

AN:

51350

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00895

AC:

9947

AN:

1111554

Other (OTH)

AF:

0.00734

AC:

443

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

525

1050

1576

2101

2626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.00475

AC:

724

AN:

152296

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

352

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41576

American (AMR)

AF:

0.00235

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00828

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00785

AC:

534

AN:

67990

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

122

163

204

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:

0.00481

Hom.:

Bravo

AF:

0.00431

EpiCase

AF:

0.00709

EpiControl

AF:

0.00700

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MPL: BP4, BS2 -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Sep 16, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MPL c.1565+5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0046 in 279466 control chromosomes (gnomAD), predominantly at a frequency of 0.0073 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MPL causing Congenital Amegakaryocytic Thrombocytopenia (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1565+5C>T in individuals affected with Congenital Amegakaryocytic Thrombocytopenia and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014 without submitting evidence for clinical-significance assessments: one classified the variant as uncertain significance, one as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign. -

Jun 09, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital amegakaryocytic thrombocytopenia

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital amegakaryocytic thrombocytopenia 1

Uncertain:1

May 31, 2017

Counsyl

Significance:Uncertain significance

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. -

MPL-related disorder

Benign:1

Oct 12, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Thrombocythemia 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.64

PromoterAI

0.11

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.012

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

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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