3-184372478-C-T

Position:

• chr3-184372478-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.*35G>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 0.549 in 1,612,896 control chromosomes in the GnomAD database, including 252,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33975 hom., cov: 32)
  • Exomes 𝑓: 0.54 (218432 hom.)
• Consequence: THPO NM_000460.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.410

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=-0.84).
• BP6: Variant 3-184372478-C-T is Benign according to our data. Variant chr3-184372478-C-T is described in ClinVar as [Benign]. Clinvar id is 344369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184372478-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THPO	NM_000460.4	c.*35G>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.*35G>A		3_prime_UTR_variant	6/6		NM_000460.4	P2

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97415 AN: 151974 Hom.: 33917 Cov.: 32

Gnomad AFR AF: 0.917

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.680

GnomAD3 exomes AF: 0.559 AC: 140412 AN: 251394 Hom.: 41288 AF XY: 0.547 AC XY: 74338 AN XY: 135872

Gnomad AFR exome AF: 0.924

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.692

Gnomad EAS exome AF: 0.435

Gnomad SAS exome AF: 0.480

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.540 AC: 788670 AN: 1460806 Hom.: 218432 Cov.: 39 AF XY: 0.537 AC XY: 389956 AN XY: 726810

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.645

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.381

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.584

GnomAD4 genome AF: 0.641 AC: 97526 AN: 152090 Hom.: 33975 Cov.: 32 AF XY: 0.629 AC XY: 46729 AN XY: 74338

Gnomad4 AFR AF: 0.918

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.675

Alfa AF: 0.567 Hom.: 34300

Bravo AF: 0.678

Asia WGS AF: 0.527 AC: 1831 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocythemia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	This variant is associated with the following publications: (PMID: 11257273) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.2
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6141; hg19: chr3-184090266; COSMIC: COSV52615748; COSMIC: COSV52615748;