1-43349338-G-C

Variant names:

• chr1-43349338-G-C
• rs121913615
• NM_005373.3:c.1544G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_005373.3(MPL):​c.1544G>C​(p.Trp515Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. W515L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98
• Publications: 532 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-43349338-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14164.
• 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.

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.1544G>C	p.Trp515Ser	missense	Exon 10 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.1544G>C	p.Trp515Ser	missense	Exon 10 of 12	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.1523G>C	p.Trp508Ser	missense	Exon 10 of 12	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000638732.1	TSL:1	n.1544G>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461020 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726868

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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	Benign	0.29
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.55
Sift	Benign	0.035	D
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.61
MutPred		0.61		Loss of catalytic residue at P518 (P = 0.0247)
MVP		0.91
MPC		0.35
ClinPred		0.91	D
GERP RS		4.9
PromoterAI		0.11	Neutral
Varity_R		0.34
gMVP		0.53
Mutation Taster		=42/58	disease causing

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: rs121913615; hg19: chr1-43815009;