1-43346929-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM1PM2PM5PP3_Moderate

The ENST00000372470.9(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 same amino acid change has been previously reported as Likely pathogenicin 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
ENST00000372470.9 missense

Scores

9
8
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.24
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1
Transcript ENST00000372470.9 (MPL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 435889
PM1
In a domain Fibronectin type-III 2 (size 94) in uniprot entity TPOR_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000372470.9
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 id is 2043461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MPLNM_005373.3 linkuse as main transcriptc.1303T>C p.Trp435Arg missense_variant 8/12 ENST00000372470.9 NP_005364.1 P40238-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MPLENST00000372470.9 linkuse as main transcriptc.1303T>C p.Trp435Arg missense_variant 8/121 NM_005373.3 ENSP00000361548.3 P40238-1
MPLENST00000413998.7 linkuse as main transcriptc.1282T>C p.Trp428Arg missense_variant 8/121 ENSP00000414004.3 Q5JUY5
MPLENST00000638732.1 linkuse as main transcriptn.1303T>C non_coding_transcript_exon_variant 8/101

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
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;.
MutationTaster
Benign
1.0
D;D
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

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.

Other links and lift over

dbSNP: rs1553128241; hg19: chr1-43812600; API