Variant chr1-43346404-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005373.3(MPL):c.981-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,605,630 control chromosomes in the GnomAD database, including 104,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7925 hom., cov: 31)

Exomes 𝑓: 0.36 ( 96186 hom. )

Consequence

MPL
NM_005373.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.575

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-43346404-G-A is Benign according to our data. Variant chr1-43346404-G-A is described in ClinVar as [Benign]. Clinvar id is 259760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPL	NM_005373.3 linkuse as main transcript	c.981-41G>A		intron_variant		ENST00000372470.9

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
MPL	ENST00000372470.9 linkuse as main transcript	c.981-41G>A	intron_variant	1	NM_005373.3	P1	P40238-1
MPL	ENST00000413998.7 linkuse as main transcript	c.960-41G>A	intron_variant	1
MPL	ENST00000638732.1 linkuse as main transcript	n.981-41G>A	intron_variant, non_coding_transcript_variant	1

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47424

AN:

151876

Hom.:

7921

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.406

Gnomad EAS

AF:

0.0734

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.404

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.367

GnomAD3 exomes

AF:

0.303

AC:

74837

AN:

246656

Hom.:

12659

AF XY:

0.301

AC XY:

40142

AN XY:

133326

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.303

Gnomad ASJ exome

AF:

0.415

Gnomad EAS exome

AF:

0.0676

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.355

AC:

516068

AN:

1453636

Hom.:

96186

Cov.:

AF XY:

0.350

AC XY:

252955

AN XY:

723352

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.314

Gnomad4 ASJ exome

AF:

0.411

Gnomad4 EAS exome

AF:

0.0977

Gnomad4 SAS exome

AF:

0.149

Gnomad4 FIN exome

AF:

0.324

Gnomad4 NFE exome

AF:

0.386

Gnomad4 OTH exome

AF:

0.340

GnomAD4 genome

AF:

0.312

AC:

47458

AN:

151994

Hom.:

7925

Cov.:

AF XY:

0.308

AC XY:

22837

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.366

Gnomad4 ASJ

AF:

0.406

Gnomad4 EAS

AF:

0.0734

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.332

Gnomad4 NFE

AF:

0.373

Gnomad4 OTH

AF:

0.365

Alfa

AF:

0.368

Hom.:

10802

Bravo

AF:

0.313

Asia WGS

AF:

0.131

AC:

456

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

9.8

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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