1-43352220-C-T

Variant names:

• chr1-43352220-C-T
• rs146372205
• NM_005373.3:c.1570C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_005373.3(MPL):​c.1570C>T​(p.Leu524Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,612,950 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. L524L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: MPL NM_005373.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.115
• Publications: 1 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]

CDC20-DT (HGNC:55681): (CDC20 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-43352220-C-T is Benign according to our data. Variant chr1-43352220-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 297408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.115 with no splicing effect.

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.1570C>T	p.Leu524Leu	synonymous	Exon 11 of 12	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.1570C>T	p.Leu524Leu	synonymous	Exon 11 of 12	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.1549C>T	p.Leu517Leu	synonymous	Exon 11 of 12	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000967221.1		c.1585C>T	p.Leu529Leu	synonymous	Exon 11 of 12	ENSP00000637280.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000400 AC: 100 AN: 250252 AF XY: 0.000421

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000775

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000526 AC: 768 AN: 1460660 Hom.: 1 Cov.: 32 AF XY: 0.000504 AC XY: 366 AN XY: 726686

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000516 AC: 27 AN: 52296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000641 AC: 713 AN: 1111924

Other (OTH) AF: 0.000282 AC: 17 AN: 60382

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74458

African (AFR) AF: 0.000217 AC: 9 AN: 41558

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000504 Hom.: 0

Bravo AF: 0.000348

EpiCase AF: 0.000382

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.2
DANN	Benign	0.64
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs146372205; hg19: chr1-43817891;