chr1-43338669-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_005373.3(MPL):c.340G>A(p.Val114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,614,118 control chromosomes in the GnomAD database, including 766 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.022 ( 48 hom., cov: 32)

Exomes 𝑓: 0.030 ( 718 hom. )

Consequence

MPL
NM_005373.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0370

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005373.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.39478 (below the threshold of 3.09). Trascript score misZ: 1.6963 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital amegakaryocytic thrombocytopenia 1, congenital amegakaryocytic thrombocytopenia, familial thrombocytosis, thrombocythemia 2, hereditary isolated aplastic anemia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022851825).

BP6

Variant 1-43338669-G-A is Benign according to our data. Variant chr1-43338669-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134825.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Likely_benign=4, Benign=4}. Variant chr1-43338669-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3392/152246) while in subpopulation NFE AF = 0.0331 (2252/68018). AF 95% confidence interval is 0.032. There are 48 homozygotes in GnomAd4. There are 1602 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3 link	c.340G>A	p.Val114Met	missense_variant	Exon 3 of 12	ENST00000372470.9	NP_005364.1	P40238-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MPL	ENST00000372470.9 link	c.340G>A	p.Val114Met	missense_variant	Exon 3 of 12	1	NM_005373.3	ENSP00000361548.3	P40238-1
MPL	ENST00000413998.7 link	c.319G>A	p.Val107Met	missense_variant	Exon 3 of 12	1		ENSP00000414004.3	Q5JUY5
MPL	ENST00000638732.1 link	n.340G>A		non_coding_transcript_exon_variant	Exon 3 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3392

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.0288

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0255

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0246

AC:

6191

AN:

251490

AF XY:

0.0262

show subpopulations

Gnomad AFR exome

AF:

0.00634

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.0338

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0299

AC:

43742

AN:

1461872

Hom.:

718

Cov.:

AF XY:

0.0300

AC XY:

21851

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00457

AC:

153

AN:

33480

Gnomad4 AMR exome

AF:

0.0158

AC:

705

AN:

44724

Gnomad4 ASJ exome

AF:

0.0217

AC:

567

AN:

26136

Gnomad4 EAS exome

AF:

0.0000504

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0320

AC:

2763

AN:

86258

Gnomad4 FIN exome

AF:

0.0207

AC:

1107

AN:

53412

Gnomad4 NFE exome

AF:

0.0330

AC:

36655

AN:

1111998

Gnomad4 Remaining exome

AF:

0.0264

AC:

1596

AN:

60396

Heterozygous variant carriers

2560

5120

7681

10241

12801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

1352

2704

4056

5408

6760

<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:

0.0223

AC:

3392

AN:

152246

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1602

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00576

AC:

0.00575598

AN:

0.00575598

Gnomad4 AMR

AF:

0.0288

AC:

0.0288085

AN:

0.0288085

Gnomad4 ASJ

AF:

0.0236

AC:

0.0236175

AN:

0.0236175

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.0255

AC:

0.0255081

AN:

0.0255081

Gnomad4 FIN

AF:

0.0173

AC:

0.0173356

AN:

0.0173356

Gnomad4 NFE

AF:

0.0331

AC:

0.0331089

AN:

0.0331089

Gnomad4 OTH

AF:

0.0227

AC:

0.0227058

AN:

0.0227058

Heterozygous variant carriers

177

354

531

708

885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0295

Hom.:

317

Bravo

AF:

0.0219

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0340

AC:

131

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0331

AC:

285

ExAC

AF:

0.0250

AC:

3040

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0362

EpiControl

AF:

0.0343

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

This variant is associated with the following publications: (PMID: 27884173, 11133753, 21228398, 24728327, 20981092, 22995991) -

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital amegakaryocytic thrombocytopenia

Pathogenic:1Benign:3

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2017

Counsyl

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not specified

Benign:2Other:1

Dec 28, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Val114Met variant in MPL is classified as likely benign because it has been identified in 3.3% (2251/68026) of European chromosomes including 48 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Benign:1

Feb 03, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.36

N;.

REVEL

Benign

0.095

Sift

Benign

0.10

T;.

Sift4G

Benign

0.083

T;.

Polyphen

0.98

D;.

Vest4

0.063

MPC

0.21

ClinPred

0.0034

GERP RS

0.012

Varity_R

0.036

gMVP

0.56

Mutation Taster

=100/0

polymorphism (auto)

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