rs28928907

Variant names:

• chr1-43338634-G-A
• rs28928907
• NM_005373.3:c.305G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-43338634-G-A
• chr1-43338634-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_005373.3(MPL):​c.305G>A​(p.Arg102His) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.43
• Publications: 48 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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: Likely_pathogenic. The variant received 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-43338633-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 644406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 1-43338634-G-A is Pathogenic according to our data. Variant chr1-43338634-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 988868.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3	c.305G>A	p.Arg102His	missense_variant	Exon 3 of 12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.305G>A	p.Arg102His	missense_variant	Exon 3 of 12	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7	c.284G>A	p.Arg95His	missense_variant	Exon 3 of 12	1		ENSP00000414004.3
MPL	ENST00000638732.1	n.305G>A		non_coding_transcript_exon_variant	Exon 3 of 10	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251490 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Pathogenic:1

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 102 of the MPL protein (p.Arg102His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 32703794). ClinVar contains an entry for this variant (Variation ID: 988868). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPL protein function. This variant disrupts the p.Arg102 amino acid residue in MPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11972523, 16470591, 21659346, 28859041). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		5.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.33
Sift	Benign	0.29	T;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.98	D;.
Vest4		0.68
MutPred		0.83		Gain of catalytic residue at E99 (P = 0.1253);.;
MVP		0.71
MPC		0.84
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.099
gMVP		0.68
Mutation Taster		=66/34	polymorphism

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: rs28928907; hg19: chr1-43804305; COSMIC: COSV100991317;