rs121913614

Positions:

• chr1-43349308-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The ENST00000372470.9(MPL):​c.1514G>A​(p.Ser505Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S505C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPL ENST00000372470.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.68

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-43349307-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376029.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 1-43349308-G-A is Pathogenic according to our data. Variant chr1-43349308-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14163.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPL	NM_005373.3	c.1514G>A	p.Ser505Asn	missense_variant	10/12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.1514G>A	p.Ser505Asn	missense_variant	10/12	1	NM_005373.3	ENSP00000361548	P1
MPL	ENST00000413998.7	c.1493G>A	p.Ser498Asn	missense_variant	10/12	1		ENSP00000414004
MPL	ENST00000638732.1	n.1514G>A		non_coding_transcript_exon_variant	10/10	1
MPL	ENST00000643351.1	c.47G>A	p.Ser16Asn	missense_variant	1/4			ENSP00000495154

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jun 17, 2021

- -

Thrombocythemia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 08, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.010	A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.22
Sift	Benign	0.12	T;.
Sift4G	Benign	0.14	T;.
Polyphen		0.0020	B;.
Vest4		0.34
MutPred		0.76		Loss of catalytic residue at G503 (P = 0.2195);.;
MVP		0.77
MPC		0.18
ClinPred		0.43	T
GERP RS		2.6
Varity_R		0.16
gMVP		0.42

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

Other links and lift over

dbSNP: rs121913614; hg19: chr1-43814979; COSMIC: COSV65244631;