NM_005373.3:c.1602C>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D534Y) has been classified 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
• Publications: 0 publications found

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]

CDC20-DT (HGNC:55681): (CDC20 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.39478 (below the threshold of 3.09). Trascript score misZ: 1.6963 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary isolated aplastic anemia, congenital amegakaryocytic thrombocytopenia, thrombocythemia 2, congenital amegakaryocytic thrombocytopenia 1, familial thrombocytosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2328788).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005373.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPL	NM_005373.3	MANE Select	c.1602C>G	p.Asp534Glu	missense	Exon 11 of 12	NP_005364.1	P40238-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPL	ENST00000372470.9	TSL:1 MANE Select	c.1602C>G	p.Asp534Glu	missense	Exon 11 of 12	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.1581C>G	p.Asp527Glu	missense	Exon 11 of 12	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000967221.1		c.1617C>G	p.Asp539Glu	missense	Exon 11 of 12	ENSP00000637280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.099
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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

hg19: chr1-43817923;