1-43352252-C-G

Variant names:

• chr1-43352252-C-G
• NM_005373.3:c.1602C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005373.3(MPL):​c.1602C>G​(p.Asp534Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0990

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 121) in uniprot entity TPOR_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_005373.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2328788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3	c.1602C>G	p.Asp534Glu	missense_variant	Exon 11 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.1602C>G	p.Asp534Glu	missense_variant	Exon 11 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7	c.1581C>G	p.Asp527Glu	missense_variant	Exon 11 of 12	1		ENSP00000414004.3
MPL	ENST00000643351.1	c.258C>G	p.Asp86Glu	missense_variant	Exon 3 of 4			ENSP00000495154.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Uncertain:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 534 of the MPL protein (p.Asp534Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MPL-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MPL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.55	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.58	P;.
Vest4		0.20
MutPred		0.27		Gain of catalytic residue at D534 (P = 0.1635);.;
MVP		0.78
MPC		0.42
ClinPred		0.39	T
GERP RS		3.0
Varity_R		0.080
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-43817923;