rs141311765

Positions:

• chr1-43340027-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_005373.3(MPL):​c.754T>C​(p.Tyr252His) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3 O:1
• Conservation: PhyloP100: 4.39

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_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005373.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.029650927).
• BP6: Variant 1-43340027-T-C is Benign according to our data. Variant chr1-43340027-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134834.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPL	NM_005373.3	c.754T>C	p.Tyr252His	missense_variant	5/12	ENST00000372470.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPL	ENST00000372470.9	c.754T>C	p.Tyr252His	missense_variant	5/12	1	NM_005373.3	P1
MPL	ENST00000413998.7	c.733T>C	p.Tyr245His	missense_variant	5/12	1
MPL	ENST00000638732.1	n.754T>C		non_coding_transcript_exon_variant	5/10	1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250424 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135468

Gnomad AFR exome AF: 0.00501

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66 AN XY: 727244

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74502

Gnomad4 AFR AF: 0.00377

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.00144

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000371 AC: 45

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2023	Variant summary: MPL c.754T>C (p.Tyr252His) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 250424 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MPL causing Congenital Amegakaryocytic Thrombocytopenia phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.754T>C has been reported in the literature as a VUS in settings of multigene panel testing among cohorts of individuals with Inherited bone marrow failure syndromes (IBMFSs) who remained as "unclassified" based on the reported findings (example, Galvez_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Amegakaryocytic Thrombocytopenia or MPL-related Inherited bone marrow failure syndromes (IBMFSs). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2021	This sequence change does not appear to have been previously described in patients with MPL-related disorders and has been described in the gnomAD database with a high population frequency of 0.43% in the African subpopulation (dbSNP rs141311765). The p.Tyr252His change affects a highly conserved amino acid residue located in a domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Tyr252His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Tyr252His change remains unknown at this time. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Congenital amegakaryocytic thrombocytopenia Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MPL c.754T>C (p.Tyr252His) missense variant has been reported in one study in which it was identified in a heterozygous state in a child with essential thrombocythemia (Lambert et al. 2012). The patient also carried two other variants in the MPL gene in a heterozygous state, one of which was a known polymorphism and the other was found deep in an intron and thought unlikely to be responsible for the phenotype. The variant has not been reported in individuals with congenital amegakaryocytic thrombocytopenia. Control data are unavailable for the p.Tyr252His variant which is reported at a frequency of 0.0052 in the African American population of the Exome Sequencing Project. The Tyr252 residue is noted to be conserved. Wild type and variant MPL were introduced into cytokine-dependent BaF3 cells through retroviral transduction. Cells stably expressing the p.Tyr252His variant allele exhibited increased proliferation in response to thrombopoietin (TPO), in particular at low concentration, when compared to wild type. Upon cytokine withdrawal, cells expressing the variant survived better than those expressing a wild type allele. These data suggest that the p.Tyr252His variant results in increased TPO/MPL-mediated cell growth and may contribute to the development of essential thrombocythemia in vivo (Lambert et al. 2012). In a genome wide association study of nearly 15,000 African Americans, the p.Tyr252His variant was significantly associated with higher platelet counts (Auer et al. 2012). Based on the limited evidence, the p.Tyr152His variant is classified as a variant of unknown significance for essential thrombocythemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.030	T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.57	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.030	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.88
MVP		0.87
MPC		0.86
ClinPred		0.086	T
GERP RS		4.8
Varity_R		0.17
gMVP		0.75

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: rs141311765; hg19: chr1-43805698; COSMIC: COSV65244516;