3-184372454-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.*59G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,604,796 control chromosomes in the GnomAD database, including 2,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (313 hom., cov: 33)
  • Exomes 𝑓: 0.057 (2613 hom.)
• Consequence: THPO NM_000460.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.600

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=-0.79).
• BP6: Variant 3-184372454-C-T is Benign according to our data. Variant chr3-184372454-C-T is described in ClinVar as [Benign]. Clinvar id is 344368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THPO	NM_000460.4	c.*59G>A		3_prime_UTR_variant	6/6	ENST00000647395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THPO	ENST00000647395.1	c.*59G>A		3_prime_UTR_variant	6/6		NM_000460.4	P2

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9592 AN: 152152 Hom.: 313 Cov.: 33

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0722

GnomAD4 exome AF: 0.0567 AC: 82360 AN: 1452526 Hom.: 2613 Cov.: 28 AF XY: 0.0574 AC XY: 41518 AN XY: 723220

Gnomad4 AFR exome AF: 0.0852

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.0568

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.0563

Gnomad4 OTH exome AF: 0.0624

GnomAD4 genome AF: 0.0630 AC: 9594 AN: 152270 Hom.: 313 Cov.: 33 AF XY: 0.0617 AC XY: 4592 AN XY: 74450

Gnomad4 AFR AF: 0.0796

Gnomad4 AMR AF: 0.0699

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.0636

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0578

Gnomad4 OTH AF: 0.0714

Alfa AF: 0.0612 Hom.: 37

Bravo AF: 0.0671

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocythemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2018

This variant is associated with the following publications: (PMID: 27668658) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.4
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78565404; hg19: chr3-184090242;