rs16830693

chr1-43339569-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005373.3(MPL):c.690A>G(p.Glu230=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 1,614,174 control chromosomes in the GnomAD database, including 1,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (299 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1033 hom.)
• Consequence: MPL NM_005373.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005475
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 2.12

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-43339569-A-G is Benign according to our data. Variant chr1-43339569-A-G is described in ClinVar as [Benign]. Clinvar id is 134827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43339569-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPL	NM_005373.3	c.690A>G	p.Glu230=	splice_region_variant, synonymous_variant	4/12	ENST00000372470.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPL	ENST00000372470.9	c.690A>G	p.Glu230=	splice_region_variant, synonymous_variant	4/12	1	NM_005373.3	P1
MPL	ENST00000413998.7	c.669A>G	p.Glu223=	splice_region_variant, synonymous_variant	4/12	1
MPL	ENST00000638732.1	n.690A>G		splice_region_variant, non_coding_transcript_exon_variant	4/10	1

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7604 AN: 152182 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0312

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0344 AC: 8641 AN: 251242 Hom.: 224 AF XY: 0.0348 AC XY: 4732 AN XY: 135858

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0234

Gnomad SAS exome AF: 0.0477

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0337 AC: 49255 AN: 1461874 Hom.: 1033 Cov.: 32 AF XY: 0.0338 AC XY: 24613 AN XY: 727240

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0154

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.0389

Gnomad4 NFE exome AF: 0.0319

Gnomad4 OTH exome AF: 0.0390

GnomAD4 genome AF: 0.0501 AC: 7623 AN: 152300 Hom.: 299 Cov.: 32 AF XY: 0.0488 AC XY: 3634 AN XY: 74470

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.0535

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.0312

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0327 Hom.: 233

Bravo AF: 0.0506

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0277

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Thrombocythemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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
BayesDel_noAF	Benign	-0.48
Cadd	Benign	8.3
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.072
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: rs16830693; hg19: chr1-43805240; COSMIC: COSV65244224;