rs12731981

Variant names:

• chr1-43338669-G-A
• rs12731981
• NM_005373.3:c.340G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 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. 15/21 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:11 O:1
• Conservation: PhyloP100: 0.0370
• Publications: 34 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: Benign. The variant received -10 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, 5 uncertain in NM_005373.3
• 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 hereditary isolated aplastic anemia, congenital amegakaryocytic thrombocytopenia, thrombocythemia 2, congenital amegakaryocytic thrombocytopenia 1, familial thrombocytosis.
• 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 VariationId is 134825.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 AD,AR gene

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.340G>A	p.Val114Met	missense	Exon 3 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.340G>A	p.Val114Met	missense	Exon 3 of 12	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.319G>A	p.Val107Met	missense	Exon 3 of 12	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000638732.1	TSL:1	n.340G>A		non_coding_transcript_exon	Exon 3 of 10

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

GnomAD2 exomes AF: 0.0246 AC: 6191 AN: 251490 AF XY: 0.0262

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 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

African (AFR) AF: 0.00457 AC: 153 AN: 33480

American (AMR) AF: 0.0158 AC: 705 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 567 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0320 AC: 2763 AN: 86258

European-Finnish (FIN) AF: 0.0207 AC: 1107 AN: 53412

Middle Eastern (MID) AF: 0.0336 AC: 194 AN: 5768

European-Non Finnish (NFE) AF: 0.0330 AC: 36655 AN: 1111998

Other (OTH) AF: 0.0264 AC: 1596 AN: 60396

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

African (AFR) AF: 0.00576 AC: 239 AN: 41522

American (AMR) AF: 0.0288 AC: 441 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4822

European-Finnish (FIN) AF: 0.0173 AC: 184 AN: 10614

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0331 AC: 2252 AN: 68018

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0295 Hom.: 317

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
1	-	2	Congenital amegakaryocytic thrombocytopenia (3)
-	-	2	not specified (3)
-	-	1	Congenital amegakaryocytic thrombocytopenia 1 (1)
-	-	1	Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.037
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
Mutation Taster		=100/0	polymorphism (auto)

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