1-43339428-G-A

Position:

• chr1-43339428-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_005373.3(MPL):​c.549G>A​(p.Thr183=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T183T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: MPL NM_005373.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: -0.509

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-43339428-G-A is Benign according to our data. Variant chr1-43339428-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.509 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPL	NM_005373.3	c.549G>A	p.Thr183=	synonymous_variant	4/12	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.549G>A	p.Thr183=	synonymous_variant	4/12	1	NM_005373.3	ENSP00000361548	P1
MPL	ENST00000413998.7	c.528G>A	p.Thr176=	synonymous_variant	4/12	1		ENSP00000414004
MPL	ENST00000638732.1	n.549G>A		non_coding_transcript_exon_variant	4/10	1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000433 AC: 109 AN: 251460 Hom.: 1 AF XY: 0.000434 AC XY: 59 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000418 AC: 611 AN: 1461894 Hom.: 1 Cov.: 32 AF XY: 0.000406 AC XY: 295 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000452

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74350

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000351

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MPL: BP4, BP7 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MPL p.Thr183Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs147130173) and in ClinVar (classified as a VUS in 2016 by Genetics Services Laboratory, University of Chicago). The variant was identified in control databases in 114 of 282848 chromosomes (1 homozygous) at a frequency of 0.000403 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 38 of 35438 chromosomes (freq: 0.001072), Ashkenazi Jewish in 6 of 10370 chromosomes (freq: 0.000579), European (non-Finnish) in 58 of 129164 chromosomes (freq: 0.000449), Other in 3 of 7228 chromosomes (freq: 0.000415), South Asian in 7 of 30616 chromosomes (freq: 0.000229), African in 1 of 24962 chromosomes (freq: 0.00004) and European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence however 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, GeneSplicer) predict a greater than 10% difference in splicing and the gain of a 3’ splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 08, 2021

- -

MPL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital amegakaryocytic thrombocytopenia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 14, 2020

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.0
DANN	Benign	0.51

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: rs147130173; hg19: chr1-43805099;