rs117656396

Positions:

• chr1-43340066-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005373.3(MPL):​c.793C>T​(p.Leu265Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,182 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L265L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (6 hom.)
• Consequence: MPL NM_005373.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.605

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044531524).
• BP6: Variant 1-43340066-C-T is Benign according to our data. Variant chr1-43340066-C-T is described in ClinVar as [Benign]. Clinvar id is 134832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000696 (106/152322) while in subpopulation EAS AF= 0.0197 (102/5174). AF 95% confidence interval is 0.0166. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPL	NM_005373.3	c.793C>T	p.Leu265Phe	missense_variant	5/12	ENST00000372470.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPL	ENST00000372470.9	c.793C>T	p.Leu265Phe	missense_variant	5/12	1	NM_005373.3	P1
MPL	ENST00000413998.7	c.772C>T	p.Leu258Phe	missense_variant	5/12	1
MPL	ENST00000638732.1	n.793C>T		non_coding_transcript_exon_variant	5/10	1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00141 AC: 354 AN: 251000 Hom.: 2 AF XY: 0.00119 AC XY: 162 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0190

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000330 AC: 482 AN: 1461860 Hom.: 6 Cov.: 32 AF XY: 0.000281 AC XY: 204 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0108

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000860 Hom.: 2

Bravo AF: 0.000801

ExAC AF: 0.00121 AC: 147

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital amegakaryocytic thrombocytopenia Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 26, 2019	- -

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
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.84	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.44	N;.
REVEL	Benign	0.23
Sift	Benign	0.25	T;.
Sift4G	Uncertain	0.013	D;.
Polyphen		0.024	B;.
Vest4		0.13
MVP		0.82
MPC		0.23
ClinPred		0.013	T
GERP RS		4.1
Varity_R		0.060
gMVP		0.17

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: rs117656396; hg19: chr1-43805737;