rs16830693

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005373.3(MPL):c.690A>G(p.Glu230Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 1,614,174 control chromosomes in the GnomAD database, including 1,332 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 Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 299 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1033 hom. )

Consequence

MPL
NM_005373.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0005475

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 2.12

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 1-43339569-A-G is Benign according to our data. Variant chr1-43339569-A-G is described in ClinVar as Benign. ClinVar VariationId is 134827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.12 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3 link	c.690A>G	p.Glu230Glu	splice_region_variant, synonymous_variant	Exon 4 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MPL	ENST00000372470.9 link	c.690A>G	p.Glu230Glu	splice_region_variant, synonymous_variant	Exon 4 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7 link	c.669A>G	p.Glu223Glu	splice_region_variant, synonymous_variant	Exon 4 of 12	1		ENSP00000414004.3
MPL	ENST00000638732.1 link	n.690A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.0500

AC:

7604

AN:

152182

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0196

Gnomad SAS

AF:

0.0537

Gnomad FIN

AF:

0.0353

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0312

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.0344

AC:

8641

AN:

251242

AF XY:

0.0348

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.0234

Gnomad FIN exome

AF:

0.0394

Gnomad NFE exome

AF:

0.0304

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0337

AC:

49255

AN:

1461874

Hom.:

1033

Cov.:

AF XY:

0.0338

AC XY:

24613

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.106

AC:

3543

AN:

33478

American (AMR)

AF:

0.0130

AC:

582

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

324

AN:

26136

East Asian (EAS)

AF:

0.0154

AC:

611

AN:

39700

South Asian (SAS)

AF:

0.0473

AC:

4084

AN:

86256

European-Finnish (FIN)

AF:

0.0389

AC:

2080

AN:

53420

Middle Eastern (MID)

AF:

0.0378

AC:

218

AN:

5768

European-Non Finnish (NFE)

AF:

0.0319

AC:

35458

AN:

1111998

Other (OTH)

AF:

0.0390

AC:

2355

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2738

5475

8213

10950

13688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1444

2888

4332

5776

7220

<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:

0.0501

AC:

7623

AN:

152300

Hom.:

299

Cov.:

AF XY:

0.0488

AC XY:

3634

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.103

AC:

4291

AN:

41554

American (AMR)

AF:

0.0219

AC:

335

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.0199

AC:

103

AN:

5186

South Asian (SAS)

AF:

0.0535

AC:

258

AN:

4820

European-Finnish (FIN)

AF:

0.0353

AC:

375

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0312

AC:

2125

AN:

68024

Other (OTH)

AF:

0.0364

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

371

742

1112

1483

1854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0350

Hom.:

555

Bravo

AF:

0.0506

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

EpiCase

AF:

0.0280

EpiControl

AF:

0.0277

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombocythemia 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.3

(source)

DANN

Benign

0.76

PhyloP100

2.1

Mutation Taster

=43/57

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00055

dbscSNV1_RF

Benign

0.072

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