1-43337929-T-A

Variant names:

• chr1-43337929-T-A
• rs146249964
• NM_005373.3:c.79+2T>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005373.3(MPL):​c.79+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000191 in 1,609,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MPL NM_005373.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 4.03

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 1-43337929-T-A is Pathogenic according to our data. Variant chr1-43337929-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPL	NM_005373.3	c.79+2T>A		splice_donor_variant, intron_variant	Intron 1 of 11	ENST00000372470.9	NP_005364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPL	ENST00000372470.9	c.79+2T>A		splice_donor_variant, intron_variant	Intron 1 of 11	1	NM_005373.3	ENSP00000361548.3
MPL	ENST00000413998.7	c.79+2T>A		splice_donor_variant, intron_variant	Intron 1 of 11	1		ENSP00000414004.3
MPL	ENST00000638732.1	n.79+2T>A		splice_donor_variant, intron_variant	Intron 1 of 9	1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000402 AC: 97 AN: 241170 Hom.: 0 AF XY: 0.000437 AC XY: 57 AN XY: 130414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1457166 Hom.: 0 Cov.: 33 AF XY: 0.000196 AC XY: 142 AN XY: 724528

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.000548

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000654 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia Pathogenic:5

Oct 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MPL c.79+2T>A variant involves the alteration of a splice donor site in intron 1, which 5/5 splice prediction tools predict the removal this splice donor site, however, functional studies have yet to be performed to assess these predictions. This variant was found in 58/100444 control chromosomes at a frequency of 0.0005774, which does not exceed the estimated maximal expected allele frequency of a pathogenic MPL variant (0.002357). This variant has been reported in two patients with Amegakaryocytic Thrombocytopenia in homozygous state (Germeshausen_2006 and Jalas_2011). It has also been reported as germline variant in patients with Breast Cancer, Non-Small Cell Lung Cancer, Melanoma and Non-Seminomatous Germ Cell Tumor (Schrader_2016). The variant is a founder mutation in Ashkenazi Jewish population with a carrier frequency of 1 in 75 (Jalas_2011). One clinical diagnostic laboratory in ClinVar classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_005373.2(MPL):c.79+2T>A is classified as pathogenic in the context of congenital amegakaryocytic thrombocytopenia. Sources cited for classification include the following: PMID 21489838 and 16470591. Classification of NM_005373.2(MPL):c.79+2T>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79+2T>A variant in MPL has been reported in the homozygous state in 2 indi viduals with congenital amegakaryocyctic thrombocytopenia (CAMT; Germeshausen 20 06, Jalas 2011). It has also been identified in 0.8% (80/9916) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org/; dbSNP rs146249964), and is suggested to be a founder variant in th e Ashkenazi Jewish population (Jalas 2011). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alt ered splicing leading to an abnormal or absent protein. Loss of function of the MPL gene is an established mechanism of disease. In summary, although additional studies are required to fully establish its clinical significance, the c.79+2T> A variant is likely pathogenic. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NG_007525.1(NM_005373.2):c.79+2T>A in the MPL gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located on a biological transcript and leads to exon skipping or use of a cryptic splice site disrupts reading frame and is therefore predicted to undergo NMD. It has been reported as a founder mutation the Ashkenazi Jewish population (PMID: 21489838). This variant has been reported in homozygous state in two patients with Amegakaryocytic Thrombocytopenia (PMID: 16470591; 21489838). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM3; PP4 -

not provided Pathogenic:4

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MPL c.79+2T>A variant was identified in the literature as a homozygous variant in two unrelated patients with congenital amegakaryocytic thrombocytopenia (CAMT) (Germeshausen_2006_PMID:16470591; Jalas_2011_PMID:21489838). In a sample of 2018 individuals of Ashkenazi Jewish descent, the variant was found to have a carrier frequency of 1 in 75 (Jalas_2011_PMID:21489838). The variant was identified in dbSNP (ID: rs146249964) and ClinVar (classified as pathogenic by GeneDx, Integrated Genetics, Counsyl and Fulgent Genetics, and as likely pathogenic by Laboratory for Molecular Medicine, Invitae, Illumina and NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 97 of 259028 chromosomes at a frequency of 0.0003745 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 81 of 9646 chromosomes (freq: 0.008397), Other in 4 of 6556 chromosomes (freq: 0.00061) and European (non-Finnish) in 12 of 113480 chromosomes (freq: 0.000106), but was not observed in the African, Latino, East Asian, European (Finnish), or South Asian populations. The c.79+2T>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a difference in splicing and the loss of the canonical 5' splice site. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

May 24, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26822949, 21489838, 31064749, 24728327, 16470591, 27415407, 26556299, 29625052, 31589614) -

Nov 04, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the MPL gene demonstrated a sequence change in the canonical splice donor site of intron 1, c.79+2T>A. This sequence change has been described in the gnomAD database with an overall frequency of 0.03% (dbSNP rs146249964) and a frequency of 0.8% in the Ashkenazi Jewish population. The variant is regarded as a founder mutation in the Ashkenazi Jewish population with a carrier frequency of 1 in 75 (PMID: 21489838). This sequence change is predicted to disrupt RNA splicing and likely result in an absent or disrupted protein product. This sequence change has been previously reported in the homozygous state in individuals with congenital amegakaryocytic thrombocytopenia (PMID: 16470591, 21489838). Collectively these evidences suggest that, the c.79+2T>A change is pathogenic. -

MPL-related disorder Pathogenic:2

Dec 14, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MPL c.79+2T>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.79+2T>A variant was identified in a homozygous state in two individuals with congenital amegakaryocytic thrombocytopenia (CAMT) and in a heterozygous state in the unaffected parents of one of the individuals (Germeshausen et al. 2006; Jalas et al. 2011). The variant has not been reported in the literature in association with autosomal dominant essential thrombocythemia. The c.79+2T>A variant was absent from 50 control individuals but is reported at a frequency of 0.00057 in the European (non-Finnish) population from the Exome Aggregation Consortium. In a study of 2018 randomly selected individuals of Ashkenazi Jewish descent, Jalas et al. (2011) established a carrier frequency for the c.79+2T>A variant of one in 75. Haplotype analysis in this study suggested that the c.79+2T>A variant is a founder variant that is part of a haplotype with two upstream variants, though presence of these upstream variants cannot be assessed by the current test. Based on the evidence and the potential impact of splice donor variants, the c.79+2T>A variant is classified as likely pathogenic for MPL-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MPL c.79+2T>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in patients with autosomal recessive congenital amegakaryocytic thrombocytopenia (Germeshausen et al. 2006. PubMed ID: 16470591; Jalas et al. 2011. PubMed ID: 21489838). The c.79+2T>A variant has also been characterized as a founder variant in the Ashkenazi Jewish population, being reported in 0.82% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (Jalas et al. 2011. PubMed ID: 21489838). However, it does not occur frequently in other gnomAD populations. Variants that disrupt the consensus splice donor site in MPL are expected to be pathogenic. This variant is interpreted as pathogenic. -

Primary myelofibrosis;C3275998:Thrombocythemia 2;C5882667:Congenital amegakaryocytic thrombocytopenia 1 Pathogenic:1

Apr 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital amegakaryocytic thrombocytopenia 1 Pathogenic:1

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with recessive thrombocytopenia, congenital amegakaryocytic (MIM#604498) and dominant thrombocythemia 2, (MIM#601977), respectively (PMID: 28955303, PMID: 26423830). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This variant (c.79+1G>T) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic or likely pathogenic, and is described as a founder within the Ashkenazi Jewish population (ClinVar, PMID: 32703794, PMID: 21489838). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Primary myelofibrosis Pathogenic:1

May 23, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This c.79+2T>A variant has been previously reported as disease-causing in patients with CAMT (congenital amegakaryocytic thrombocytopenia) [PMID 16470591, 21489838] -

Thrombocytopenia Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Pathogenic:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 1 of the MPL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs146249964, gnomAD 0.8%). Disruption of this splice site has been observed in individual(s) with congenital amegakaryocytic thrombocytopenia (PMID: 16470591, 21489838). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 21489838). ClinVar contains an entry for this variant (Variation ID: 135563). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	30
DANN	Uncertain	0.98
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.83	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146249964; hg19: chr1-43803600;