rs2280740

Variant names:

• chr3-184375739-C-T
• rs2280740
• NM_000460.4:c.142-138G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000460.4(THPO):​c.142-138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0934 in 1,480,742 control chromosomes in the GnomAD database, including 6,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (783 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6172 hom.)
• Consequence: THPO NM_000460.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• Publications: 9 publications found

Genes affected

THPO (HGNC:11795): (thrombopoietin) Megakaryocytopoiesis is the cellular development process that leads to platelet production. The main functional protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene. Mutations in this gene are the cause of thrombocythemia 1. Alternative promoter usage and differential splicing result in multiple transcript variants differing in the 5' UTR and/or coding region. Multiple AUG codons upstream of the main open reading frame (ORF) have been identified, and these upstream AUGs inhibit translation of the main ORF at different extent. [provided by RefSeq, Feb 2014]

THPO Gene-Disease associations (from GenCC):

• thrombocythemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• congenital amegakaryocytic thrombocytopenia

  Inheritance: SD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• thrombocytopenia 9

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• familial thrombocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary thrombocytosis with transverse limb defect

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR 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=-0.83).
• BP6: Variant 3-184375739-C-T is Benign according to our data. Variant chr3-184375739-C-T is described in ClinVar as Benign. ClinVar VariationId is 1265627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000460.4. 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
	THPO	NM_000460.4	MANE Select	c.142-138G>A		intron	N/A	NP_000451.1	P40225-1
	THPO	NM_001290003.1		c.562-138G>A		intron	N/A	NP_001276932.1	A0A3B3ITS0
	THPO	NM_001289998.1		c.142-138G>A		intron	N/A	NP_001276927.1	P40225-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THPO	ENST00000647395.1	MANE Select	c.142-138G>A		intron	N/A	ENSP00000494504.1	P40225-1
	THPO	ENST00000445696.6	TSL:1	c.142-138G>A		intron	N/A	ENSP00000410763.2	P40225-2
	THPO	ENST00000421442.2	TSL:1	c.142-138G>A		intron	N/A	ENSP00000411704.2	F8W6L1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15215 AN: 152014 Hom.: 782 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0749

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0730

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0882

Gnomad OTH AF: 0.0958

GnomAD4 exome AF: 0.0926 AC: 123030 AN: 1328610 Hom.: 6172 Cov.: 20 AF XY: 0.0915 AC XY: 61057 AN XY: 666964

African (AFR) AF: 0.111 AC: 3389 AN: 30610

American (AMR) AF: 0.153 AC: 6623 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.0690 AC: 1740 AN: 25216

East Asian (EAS) AF: 0.152 AC: 5906 AN: 38892

South Asian (SAS) AF: 0.0711 AC: 5858 AN: 82358

European-Finnish (FIN) AF: 0.108 AC: 5642 AN: 52478

Middle Eastern (MID) AF: 0.0736 AC: 387 AN: 5258

European-Non Finnish (NFE) AF: 0.0892 AC: 88673 AN: 994606

Other (OTH) AF: 0.0860 AC: 4812 AN: 55970

GnomAD4 genome AF: 0.100 AC: 15229 AN: 152132 Hom.: 783 Cov.: 32 AF XY: 0.101 AC XY: 7508 AN XY: 74358

African (AFR) AF: 0.110 AC: 4550 AN: 41494

American (AMR) AF: 0.128 AC: 1957 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0749 AC: 260 AN: 3470

East Asian (EAS) AF: 0.139 AC: 720 AN: 5176

South Asian (SAS) AF: 0.0730 AC: 352 AN: 4820

European-Finnish (FIN) AF: 0.108 AC: 1136 AN: 10558

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0882 AC: 5996 AN: 68012

Other (OTH) AF: 0.0938 AC: 198 AN: 2110

Alfa AF: 0.0926 Hom.: 917

Bravo AF: 0.103

Asia WGS AF: 0.0990 AC: 346 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2280740; hg19: chr3-184093527;