3-184372478-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.410

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

thrombocythemia 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital amegakaryocytic thrombocytopenia
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
familial thrombocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary isolated aplastic anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary thrombocytosis with transverse limb defect
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital amegakaryocytic thrombocytopenia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

THPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 344369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THPO	NM_000460.4 link	c.*35G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000647395.1	NP_000451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THPO	ENST00000647395.1 link	c.*35G>A		3_prime_UTR_variant	Exon 6 of 6		NM_000460.4	ENSP00000494504.1		P40225-1

Frequencies

GnomAD3 genomes

AF:

0.641

AC:

97415

AN:

151974

Hom.:

33917

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.559

AC:

140412

AN:

251394

AF XY:

0.547

show subpopulations

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 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.:

AF XY:

0.537

AC XY:

389956

AN XY:

726810

show subpopulations

African (AFR)

AF:

0.931

AC:

31150

AN:

33472

American (AMR)

AF:

0.645

AC:

28825

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

18034

AN:

26134

East Asian (EAS)

AF:

0.447

AC:

17736

AN:

39694

South Asian (SAS)

AF:

0.479

AC:

41281

AN:

86198

European-Finnish (FIN)

AF:

0.381

AC:

20328

AN:

53408

Middle Eastern (MID)

AF:

0.713

AC:

4022

AN:

5638

European-Non Finnish (NFE)

AF:

0.533

AC:

592080

AN:

1111192

Other (OTH)

AF:

0.584

AC:

35214

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

20649

41298

61947

82596

103245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16902

33804

50706

67608

84510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.641

AC:

97526

AN:

152090

Hom.:

33975

Cov.:

AF XY:

0.629

AC XY:

46729

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.918

AC:

38113

AN:

41534

American (AMR)

AF:

0.652

AC:

9954

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

2380

AN:

3470

East Asian (EAS)

AF:

0.439

AC:

2266

AN:

5162

South Asian (SAS)

AF:

0.485

AC:

2336

AN:

4816

European-Finnish (FIN)

AF:

0.364

AC:

3845

AN:

10558

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.537

AC:

36496

AN:

67966

Other (OTH)

AF:

0.675

AC:

1421

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1536

3073

4609

6146

7682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.578

Hom.:

81865

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

LINK: link

Submissions by phenotype

Thrombocythemia 1

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:2

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11257273) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.2

(source)

DANN

Benign

0.49

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over