rs41269541

Positions:

chr1-43349364-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005373.3(MPL):c.1565+5C>T variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 44 hom. )

Consequence

MPL
NM_005373.3 splice_region, intron

Scores

Splicing: ADA: 0.00001505

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11O:1

Conservation

PhyloP100: 0.644

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 1-43349364-C-T is Benign according to our data. Variant chr1-43349364-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135564.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=1, Benign=4}. Variant chr1-43349364-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPL	NM_005373.3 linkuse as main transcript	c.1565+5C>T		splice_region_variant, intron_variant		ENST00000372470.9	NP_005364.1	P40238-1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MPL	ENST00000372470.9 linkuse as main transcript	c.1565+5C>T	splice_region_variant, intron_variant		1	NM_005373.3	ENSP00000361548.3	P40238-1
MPL	ENST00000413998.7 linkuse as main transcript	c.1544+5C>T	splice_region_variant, intron_variant		1		ENSP00000414004.3	Q5JUY5
MPL	ENST00000638732.1 linkuse as main transcript	n.1570C>T	non_coding_transcript_exon_variant	10/10	1
MPL	ENST00000643351.1 linkuse as main transcript	c.95+5C>T	splice_region_variant, intron_variant				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

GnomAD3 exomes

AF:

0.00451

AC:

1119

AN:

248126

Hom.:

AF XY:

0.00442

AC XY:

595

AN XY:

134476

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 SAS exome

AF:

0.00118

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

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.000881

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.00699

Gnomad4 NFE exome

AF:

0.00895

Gnomad4 OTH exome

AF:

0.00734

GnomAD4 genome

AF:

0.00475

AC:

724

AN:

152296

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

352

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00828

Gnomad4 NFE

AF:

0.00785

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00550

Hom.:

Bravo

AF:

0.00431

EpiCase

AF:

0.00709

EpiControl

AF:

0.00700

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MPL: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Congenital amegakaryocytic thrombocytopenia

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2022	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

MPL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

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

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