3-184372031-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000460.4(THPO):c.*482A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0614 in 170,186 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.063 (315 hom., cov: 33)
  • Exomes 𝑓: 0.048 (34 hom.)
• Consequence: THPO NM_000460.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.172

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-184372031-T-A is Benign according to our data. Variant chr3-184372031-T-A is described in ClinVar as [Benign]. Clinvar id is 344366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THPO	NM_000460.4	c.*482A>T		3_prime_UTR_variant	6/6	ENST00000647395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THPO	ENST00000647395.1	c.*482A>T		3_prime_UTR_variant	6/6		NM_000460.4	P2
THPO	ENST00000649095.1	c.*482A>T		3_prime_UTR_variant	7/7			A2

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9568 AN: 152206 Hom.: 313 Cov.: 33

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0544

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0609

Gnomad OTH AF: 0.0635

GnomAD4 exome AF: 0.0481 AC: 860 AN: 17862 Hom.: 34 Cov.: 0 AF XY: 0.0464 AC XY: 439 AN XY: 9456

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0329

Gnomad4 EAS exome AF: 0.0819

Gnomad4 SAS exome AF: 0.0362

Gnomad4 FIN exome AF: 0.0367

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.0487

GnomAD4 genome AF: 0.0630 AC: 9589 AN: 152324 Hom.: 315 Cov.: 33 AF XY: 0.0605 AC XY: 4510 AN XY: 74492

Gnomad4 AFR AF: 0.0801

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.0544

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0513

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0609

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0256 Hom.: 16

Bravo AF: 0.0641

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombocythemia 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.8
Dann	Benign	0.68

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: rs3804618; hg19: chr3-184089819;