1-43346929-T-C

Variant names:

• chr1-43346929-T-C
• rs1553128241
• NM_005373.3:c.1303T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1 PM2 PM5 PP2 PP3_Moderate

The NM_005373.3(MPL):​c.1303T>C​(p.Trp435Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W435C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• 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]

MPL Gene-Disease associations (from GenCC):

• thrombocythemia 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• congenital amegakaryocytic thrombocytopenia 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• familial thrombocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_005373.3 (MPL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-43346931-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2043461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3	c.1303T>C	p.Trp435Arg	missense_variant	Exon 8 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.1303T>C	p.Trp435Arg	missense_variant	Exon 8 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7	c.1282T>C	p.Trp428Arg	missense_variant	Exon 8 of 12	1		ENSP00000414004.3
MPL	ENST00000638732.1	n.1303T>C		non_coding_transcript_exon_variant	Exon 8 of 10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.0	M;.
PhyloP100		4.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.79		Gain of disorder (P = 0.0032);.;
MVP		0.88
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.72
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs1553128241; hg19: chr1-43812600;