NM_005373.3:c.981-41G>A

Variant names:

• chr1-43346404-G-A
• rs1760670
• NM_005373.3:c.981-41G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005373.3(MPL):​c.981-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,605,630 control chromosomes in the GnomAD database, including 104,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7925 hom., cov: 31)
  • Exomes 𝑓: 0.36 (96186 hom.)
• Consequence: MPL NM_005373.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.575
• Publications: 21 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-43346404-G-A is Benign according to our data. Variant chr1-43346404-G-A is described in ClinVar as Benign. ClinVar VariationId is 259760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPL	NM_005373.3	MANE Select	c.981-41G>A		intron	N/A	NP_005364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPL	ENST00000372470.9	TSL:1 MANE Select	c.981-41G>A		intron	N/A	ENSP00000361548.3
	MPL	ENST00000413998.7	TSL:1	c.960-41G>A		intron	N/A	ENSP00000414004.3
	MPL	ENST00000638732.1	TSL:1	n.981-41G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47424 AN: 151876 Hom.: 7921 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.303 AC: 74837 AN: 246656 AF XY: 0.301

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.0676

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.355 AC: 516068 AN: 1453636 Hom.: 96186 Cov.: 30 AF XY: 0.350 AC XY: 252955 AN XY: 723352

African (AFR) AF: 0.229 AC: 7639 AN: 33330

American (AMR) AF: 0.314 AC: 13921 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 10704 AN: 26050

East Asian (EAS) AF: 0.0977 AC: 3875 AN: 39658

South Asian (SAS) AF: 0.149 AC: 12799 AN: 85776

European-Finnish (FIN) AF: 0.324 AC: 17263 AN: 53248

Middle Eastern (MID) AF: 0.386 AC: 2143 AN: 5556

European-Non Finnish (NFE) AF: 0.386 AC: 427274 AN: 1105618

Other (OTH) AF: 0.340 AC: 20450 AN: 60098

GnomAD4 genome AF: 0.312 AC: 47458 AN: 151994 Hom.: 7925 Cov.: 31 AF XY: 0.308 AC XY: 22837 AN XY: 74256

African (AFR) AF: 0.224 AC: 9305 AN: 41450

American (AMR) AF: 0.366 AC: 5599 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1410 AN: 3470

East Asian (EAS) AF: 0.0734 AC: 379 AN: 5164

South Asian (SAS) AF: 0.139 AC: 670 AN: 4818

European-Finnish (FIN) AF: 0.332 AC: 3495 AN: 10542

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25358 AN: 67960

Other (OTH) AF: 0.365 AC: 769 AN: 2106

Alfa AF: 0.362 Hom.: 13642

Bravo AF: 0.313

Asia WGS AF: 0.131 AC: 456 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.8
DANN	Benign	0.68
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1760670; hg19: chr1-43812075; COSMIC: COSV65245058; COSMIC: COSV65245058;