rs839994

Variant names:

• chr1-43338767-C-T
• rs839994
• NM_005373.3:c.391+47C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-43338767-C-T
• chr1-43338767-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005373.3(MPL):​c.391+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,601,474 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (20 hom.)
• Consequence: MPL NM_005373.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.266
• 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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-43338767-C-T is Benign according to our data. Variant chr1-43338767-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00176 (2547/1449264) while in subpopulation MID AF = 0.0214 (121/5656). AF 95% confidence interval is 0.0183. There are 20 homozygotes in GnomAdExome4. There are 1253 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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.391+47C>T		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.391+47C>T		intron	N/A	ENSP00000361548.3	P40238-1
	MPL	ENST00000413998.7	TSL:1	c.370+47C>T		intron	N/A	ENSP00000414004.3	Q5JUY5
	MPL	ENST00000638732.1	TSL:1	n.391+47C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00274 AC: 685 AN: 249858 AF XY: 0.00265

Gnomad AFR exome AF: 0.00803

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00176 AC: 2547 AN: 1449264 Hom.: 20 Cov.: 29 AF XY: 0.00174 AC XY: 1253 AN XY: 721664

African (AFR) AF: 0.00908 AC: 302 AN: 33254

American (AMR) AF: 0.00474 AC: 212 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 333 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.000793 AC: 68 AN: 85724

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52796

Middle Eastern (MID) AF: 0.0214 AC: 121 AN: 5656

European-Non Finnish (NFE) AF: 0.00113 AC: 1242 AN: 1101520

Other (OTH) AF: 0.00447 AC: 268 AN: 59922

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152210 Hom.: 1 Cov.: 32 AF XY: 0.00414 AC XY: 308 AN XY: 74430

African (AFR) AF: 0.00879 AC: 365 AN: 41528

American (AMR) AF: 0.00614 AC: 94 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 67998

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00315 Hom.: 1

Bravo AF: 0.00460

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.4
DANN	Benign	0.71
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs839994; hg19: chr1-43804438;