chr1-43339569-A-G

Position:

chr1-43339569-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005373.3(MPL):c.690A>G(p.Glu230=) 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:7O:1

Conservation

PhyloP100: 2.12

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 made for transcript

Verdict is Benign. Variant got -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 id is 134827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43339569-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MPL	NM_005373.3 linkuse as main transcript	c.690A>G	p.Glu230=	splice_region_variant, synonymous_variant	4/12	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.690A>G	p.Glu230=	splice_region_variant, synonymous_variant	4/12	1	NM_005373.3	ENSP00000361548	P1	P40238-1
MPL	ENST00000413998.7 linkuse as main transcript	c.669A>G	p.Glu223=	splice_region_variant, synonymous_variant	4/12	1		ENSP00000414004
MPL	ENST00000638732.1 linkuse as main transcript	n.690A>G		splice_region_variant, non_coding_transcript_exon_variant	4/10	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

GnomAD3 exomes

AF:

0.0344

AC:

8641

AN:

251242

Hom.:

224

AF XY:

0.0348

AC XY:

4732

AN XY:

135858

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 SAS exome

AF:

0.0477

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

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.0130

Gnomad4 ASJ exome

AF:

0.0124

Gnomad4 EAS exome

AF:

0.0154

Gnomad4 SAS exome

AF:

0.0473

Gnomad4 FIN exome

AF:

0.0389

Gnomad4 NFE exome

AF:

0.0319

Gnomad4 OTH exome

AF:

0.0390

GnomAD4 genome

AF:

0.0501

AC:

7623

AN:

152300

Hom.:

299

Cov.:

AF XY:

0.0488

AC XY:

3634

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.0219

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.0199

Gnomad4 SAS

AF:

0.0535

Gnomad4 FIN

AF:

0.0353

Gnomad4 NFE

AF:

0.0312

Gnomad4 OTH

AF:

0.0364

Alfa

AF:

0.0327

Hom.:

233

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:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Congenital amegakaryocytic thrombocytopenia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Thrombocythemia 1

Benign:1

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

-0.48

CADD

Benign

8.3

DANN

Benign

0.76

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

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