chr1-43349364-C-T

Variant names:

• chr1-43349364-C-T
• rs41269541
• NM_005373.3:c.1565+5C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005373.3(MPL):​c.1565+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,611,486 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (44 hom.)
• Consequence: MPL NM_005373.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001505
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12 O:1
• Conservation: PhyloP100: 0.644
• Publications: 12 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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.109).
• BP6: Variant 1-43349364-C-T is Benign according to our data. Variant chr1-43349364-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00754 (11008/1459190) while in subpopulation NFE AF = 0.00895 (9947/1111554). AF 95% confidence interval is 0.0088. There are 44 homozygotes in GnomAdExome4. There are 5235 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPL	NM_005373.3	MANE Select	c.1565+5C>T		splice_region intron	N/A	NP_005364.1	P40238-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPL	ENST00000372470.9	TSL:1 MANE Select	c.1565+5C>T		splice_region intron	N/A	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.1544+5C>T		splice_region intron	N/A	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000638732.1	TSL:1	n.1570C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 724 AN: 152178 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00451 AC: 1119 AN: 248126 AF XY: 0.00442

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00795

Gnomad NFE exome AF: 0.00725

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00754 AC: 11008 AN: 1459190 Hom.: 44 Cov.: 31 AF XY: 0.00721 AC XY: 5235 AN XY: 726006

African (AFR) AF: 0.00131 AC: 44 AN: 33474

American (AMR) AF: 0.00190 AC: 85 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000881 AC: 23 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86238

European-Finnish (FIN) AF: 0.00699 AC: 359 AN: 51350

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00895 AC: 9947 AN: 1111554

Other (OTH) AF: 0.00734 AC: 443 AN: 60334

GnomAD4 genome AF: 0.00475 AC: 724 AN: 152296 Hom.: 2 Cov.: 33 AF XY: 0.00473 AC XY: 352 AN XY: 74470

African (AFR) AF: 0.00120 AC: 50 AN: 41576

American (AMR) AF: 0.00235 AC: 36 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00785 AC: 534 AN: 67990

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00481 Hom.: 0

Bravo AF: 0.00431

EpiCase AF: 0.00709

EpiControl AF: 0.00700

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (4)
-	-	2	Congenital amegakaryocytic thrombocytopenia (2)
-	1	-	Congenital amegakaryocytic thrombocytopenia 1 (1)
-	-	1	Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia (1)
-	-	1	MPL-related disorder (1)
-	-	1	Thrombocythemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.95
PhyloP100		0.64
PromoterAI		0.11	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.012
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: rs41269541; hg19: chr1-43815035;