rs121913611

Variant names:

• chr1-43340042-C-T
• rs121913611
• NM_005373.3:c.769C>T
• MPL p.Arg257Cys

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_005373.3(MPL):​c.769C>T​(p.Arg257Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001774496: The most pronounced variant effect results in impaired signal transduction (Tijssen_2008)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.86
• Publications: 23 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: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001774496: The most pronounced variant effect results in impaired signal transduction (Tijssen_2008).; SCV001201736: Experimental studies have shown that this missense change affects MPL function (PMID: 18422784, 20188141).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-43340043-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4292399.Status of the report is criteria_provided_single_submitter, 1 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 thrombocythemia 2, congenital amegakaryocytic thrombocytopenia 1, congenital amegakaryocytic thrombocytopenia, familial thrombocytosis, hereditary isolated aplastic anemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 1-43340042-C-T is Pathogenic according to our data. Variant chr1-43340042-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.769C>T	p.Arg257Cys	missense	Exon 5 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.769C>T	p.Arg257Cys	missense	Exon 5 of 12	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.748C>T	p.Arg250Cys	missense	Exon 5 of 12	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000638732.1	TSL:1	n.769C>T		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250774 AF XY: 0.0000590

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80 AN XY: 727226

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1112004

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74360

African (AFR) AF: 0.000169 AC: 7 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000117

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Congenital amegakaryocytic thrombocytopenia (3)
2	-	-	Congenital amegakaryocytic thrombocytopenia 1 (2)
1	-	-	Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia (1)
1	-	-	not provided (1)
1	-	-	Primary myelofibrosis;C3275998:Thrombocythemia 2;C5882667:Congenital amegakaryocytic thrombocytopenia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.49
gMVP		0.74
Mutation Taster		=8/92	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121913611;

hg19: chr1-43805713;

COSMIC: COSV65245660;