1-43337870-A-C

Variant names:

• chr1-43337870-A-C
• rs572208458
• NM_005373.3:c.22A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_005373.3(MPL):​c.22A>C​(p.Met8Leu) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. M8V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00400

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-43337871-T-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.07501665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3	c.22A>C	p.Met8Leu	missense_variant	Exon 1 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.22A>C	p.Met8Leu	missense_variant	Exon 1 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7	c.22A>C	p.Met8Leu	missense_variant	Exon 1 of 12	1		ENSP00000414004.3
MPL	ENST00000638732.1	n.22A>C		non_coding_transcript_exon_variant	Exon 1 of 10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22A>C (p.M8L) alteration is located in exon 1 (coding exon 1) of the MPL gene. This alteration results from a A to C substitution at nucleotide position 22, causing the methionine (M) at amino acid position 8 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.2
DANN	Benign	0.61
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.82	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.13
Sift	Benign	0.19	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.13
MutPred		0.47		Loss of catalytic residue at M8 (P = 0.1193);Loss of catalytic residue at M8 (P = 0.1193);
MVP		0.54
MPC		0.18
ClinPred		0.084	T
GERP RS		-7.7
Varity_R		0.076
gMVP		0.25

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: rs572208458; hg19: chr1-43803541;