rs2280740

Positions:

• chr3-184375739-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THPO	NM_000460.4	c.142-138G>A		intron_variant		ENST00000647395.1	NP_000451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THPO	ENST00000647395.1	c.142-138G>A		intron_variant			NM_000460.4	ENSP00000494504	P2

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

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.0690

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.0711

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0892

Gnomad4 OTH exome AF: 0.0860

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

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0749

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.0730

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0882

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.0909 Hom.: 696

Bravo AF: 0.103

Asia WGS AF: 0.0990 AC: 346 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.76

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: rs2280740; hg19: chr3-184093527;