rs546510242

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005373.3(MPL):c.1063A>G(p.Lys355Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,198 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 8 hom. )

Consequence

MPL
NM_005373.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3O:1

Conservation

PhyloP100: 1.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008490473).

BP6

Variant 1-43346527-A-G is Benign according to our data. Variant chr1-43346527-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134837.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, not_provided=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPL	NM_005373.3 linkuse as main transcript	c.1063A>G	p.Lys355Glu	missense_variant	7/12	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.1063A>G	p.Lys355Glu	missense_variant	7/12	1	NM_005373.3	ENSP00000361548	P1	P40238-1
MPL	ENST00000413998.7 linkuse as main transcript	c.1042A>G	p.Lys348Glu	missense_variant	7/12	1		ENSP00000414004
MPL	ENST00000638732.1 linkuse as main transcript	n.1063A>G		non_coding_transcript_exon_variant	7/10	1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000525

AC:

132

AN:

251480

Hom.:

AF XY:

0.000692

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00421

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000296

AC:

433

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000429

AC XY:

312

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00471

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000164

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000663

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000659

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia

Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 13, 2017	- -

not specified

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 14, 2020	DNA sequence analysis of the MPL gene demonstrated a sequence change, c.1063A>G, in exon 7 that results in an amino acid change, p.Lys355Glu. This sequence change does not appear to have been previously described in patients with MPL-related disorders and has been described in the gnomAD database with a frequency of 0.42% in South Asian populations (dbSNP rs546510242). The p.Lys355Glu change affects a moderately conserved amino acid residue located in a domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys355Glu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys355Glu change remains unknown at this time. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

MPL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.58

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.0085

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

0.97

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.20

N;.

REVEL

Benign

0.21

Sift

Benign

0.17

T;.

Sift4G

Benign

0.33

T;.

Polyphen

0.016

B;.

Vest4

0.29

MutPred

0.47

Loss of methylation at K355 (P = 0.0029);.;

MVP

0.72

MPC

0.27

ClinPred

0.063

GERP RS

2.4

Varity_R

0.063

gMVP

0.45

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