Variant chr3-184372454-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.600

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.*59G>A		3_prime_UTR_variant	6/6		NM_000460.4	P2	P40225-1

Frequencies

GnomAD3 genomes

AF:

0.0630

AC:

9592

AN:

152152

Hom.:

313

Cov.:

show subpopulations

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.:

AF XY:

0.0574

AC XY:

41518

AN XY:

723220

show subpopulations

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.:

AF XY:

0.0617

AC XY:

4592

AN XY:

74450

show subpopulations

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.:

Bravo

AF:

0.0671

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	This variant is associated with the following publications: (PMID: 27668658) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over