rs12731981

Positions:

• chr1-43338669-G-A
• chr1-43338669-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_005373.3(MPL):​c.340G>A​(p.Val114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,614,118 control chromosomes in the GnomAD database, including 766 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (48 hom., cov: 32)
  • Exomes 𝑓: 0.030 (718 hom.)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:9 O:1
• Conservation: PhyloP100: 0.0370

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 Benign. Variant got -11 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, 3 uncertain in NM_005373.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0022851825).
• BP6: Variant 1-43338669-G-A is Benign according to our data. Variant chr1-43338669-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134825.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, not_provided=1, Likely_pathogenic=1}. Variant chr1-43338669-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0223 (3392/152246) while in subpopulation NFE AF= 0.0331 (2252/68018). AF 95% confidence interval is 0.032. There are 48 homozygotes in gnomad4. There are 1602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPL	NM_005373.3	c.340G>A	p.Val114Met	missense_variant	3/12	ENST00000372470.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPL	ENST00000372470.9	c.340G>A	p.Val114Met	missense_variant	3/12	1	NM_005373.3	P1
MPL	ENST00000413998.7	c.319G>A	p.Val107Met	missense_variant	3/12	1
MPL	ENST00000638732.1	n.340G>A		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3392 AN: 152126 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0246 AC: 6191 AN: 251490 Hom.: 101 AF XY: 0.0262 AC XY: 3559 AN XY: 135920

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0205

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0301

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0338

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0299 AC: 43742 AN: 1461872 Hom.: 718 Cov.: 32 AF XY: 0.0300 AC XY: 21851 AN XY: 727242

Gnomad4 AFR exome AF: 0.00457

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.0330

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0223 AC: 3392 AN: 152246 Hom.: 48 Cov.: 32 AF XY: 0.0215 AC XY: 1602 AN XY: 74434

Gnomad4 AFR AF: 0.00576

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0309 Hom.: 166

Bravo AF: 0.0219

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0331 AC: 285

ExAC AF: 0.0250 AC: 3040

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0362

EpiControl AF: 0.0343

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia Pathogenic:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 11133753, 21228398, 24728327, 20981092, 22995991) -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 28, 2023	The p.Val114Met variant in MPL is classified as likely benign because it has been identified in 3.3% (2251/68026) of European chromosomes including 48 homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.36	N;.
REVEL	Benign	0.095
Sift	Benign	0.10	T;.
Sift4G	Benign	0.083	T;.
Polyphen		0.98	D;.
Vest4		0.063
MPC		0.21
ClinPred		0.0034	T
GERP RS		0.012
Varity_R		0.036
gMVP		0.56

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: rs12731981; hg19: chr1-43804340; COSMIC: COSV65244707;