3-184376395-A-G

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.-136T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,595,562 control chromosomes in the GnomAD database, including 219,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22606 hom., cov: 33)

Exomes 𝑓: 0.52 ( 196703 hom. )

Consequence

THPO
NM_000460.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.565

Publications

15 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=-0.69).

BP6

Variant 3-184376395-A-G is Benign according to our data. Variant chr3-184376395-A-G is described in ClinVar as Benign. ClinVar VariationId is 344376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THPO	NM_000460.4 link	c.-136T>C		5_prime_UTR_variant	Exon 2 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.-136T>C		5_prime_UTR_variant	Exon 2 of 6		NM_000460.4	ENSP00000494504.1		P40225-1

Frequencies

GnomAD3 genomes

AF:

0.539

AC:

81972

AN:

151956

Hom.:

22585

Cov.:

show subpopulations

Gnomad AFR

AF:

0.602

Gnomad AMI

AF:

0.501

Gnomad AMR

AF:

0.613

Gnomad ASJ

AF:

0.543

Gnomad EAS

AF:

0.419

Gnomad SAS

AF:

0.423

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.585

GnomAD4 exome

AF:

0.519

AC:

749578

AN:

1443488

Hom.:

196703

Cov.:

AF XY:

0.515

AC XY:

369745

AN XY:

717472

show subpopulations

African (AFR)

AF:

0.604

AC:

19813

AN:

32794

American (AMR)

AF:

0.611

AC:

25540

AN:

41784

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

13415

AN:

25404

East Asian (EAS)

AF:

0.440

AC:

17343

AN:

39448

South Asian (SAS)

AF:

0.430

AC:

36601

AN:

85170

European-Finnish (FIN)

AF:

0.359

AC:

17310

AN:

48282

Middle Eastern (MID)

AF:

0.622

AC:

3522

AN:

5658

European-Non Finnish (NFE)

AF:

0.529

AC:

584515

AN:

1105340

Other (OTH)

AF:

0.529

AC:

31519

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

17496

34991

52487

69982

87478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16790

33580

50370

67160

83950

<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:

0.539

AC:

82043

AN:

152074

Hom.:

22606

Cov.:

AF XY:

0.529

AC XY:

39364

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.602

AC:

24959

AN:

41468

American (AMR)

AF:

0.613

AC:

9366

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

1884

AN:

3470

East Asian (EAS)

AF:

0.419

AC:

2165

AN:

5164

South Asian (SAS)

AF:

0.423

AC:

2041

AN:

4824

European-Finnish (FIN)

AF:

0.357

AC:

3779

AN:

10584

Middle Eastern (MID)

AF:

0.677

AC:

199

AN:

294

European-Non Finnish (NFE)

AF:

0.529

AC:

35962

AN:

67964

Other (OTH)

AF:

0.584

AC:

1233

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1943

3885

5828

7770

9713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.547

Hom.:

29107

Bravo

AF:

0.563

Asia WGS

AF:

0.477

AC:

1663

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Thrombocythemia 1

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

0.56

PromoterAI

0.10

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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