rs78565404

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.*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

Publications

6 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: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
congenital amegakaryocytic thrombocytopenia
Inheritance: SD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
thrombocytopenia 9
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
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=-0.79).

BP6

Variant 3-184372454-C-T is Benign according to our data. Variant chr3-184372454-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000460.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THPO	NM_000460.4	MANE Select	c.*59G>A	3_prime_UTR	Exon 6 of 6	NP_000451.1	P40225-1
THPO	NM_001290003.1		c.*59G>A	3_prime_UTR	Exon 7 of 7	NP_001276932.1	A0A3B3ITS0
THPO	NM_001289998.1		c.*59G>A	3_prime_UTR	Exon 7 of 7	NP_001276927.1	P40225-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THPO	ENST00000647395.1	MANE Select	c.*59G>A	3_prime_UTR	Exon 6 of 6	ENSP00000494504.1	P40225-1
THPO	ENST00000445696.6	TSL:1	c.*59G>A	3_prime_UTR	Exon 6 of 6	ENSP00000410763.2	P40225-2
THPO	ENST00000421442.2	TSL:1	c.*144G>A	3_prime_UTR	Exon 6 of 6	ENSP00000411704.2	F8W6L1

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

African (AFR)

AF:

0.0852

AC:

2837

AN:

33288

American (AMR)

AF:

0.0685

AC:

3064

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2907

AN:

26082

East Asian (EAS)

AF:

0.0218

AC:

865

AN:

39650

South Asian (SAS)

AF:

0.0568

AC:

4882

AN:

85918

European-Finnish (FIN)

AF:

0.0257

AC:

1370

AN:

53370

Middle Eastern (MID)

AF:

0.0959

AC:

515

AN:

5372

European-Non Finnish (NFE)

AF:

0.0563

AC:

62175

AN:

1104136

Other (OTH)

AF:

0.0624

AC:

3745

AN:

60012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

4107

8215

12322

16430

20537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2308

4616

6924

9232

11540

<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:

0.0630

AC:

9594

AN:

152270

Hom.:

313

Cov.:

AF XY:

0.0617

AC XY:

4592

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0796

AC:

3308

AN:

41540

American (AMR)

AF:

0.0699

AC:

1070

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

356

AN:

3472

East Asian (EAS)

AF:

0.0232

AC:

120

AN:

5182

South Asian (SAS)

AF:

0.0636

AC:

307

AN:

4830

European-Finnish (FIN)

AF:

0.0219

AC:

232

AN:

10614

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0578

AC:

3932

AN:

68014

Other (OTH)

AF:

0.0714

AC:

151

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

470

940

1411

1881

2351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0612

Hom.:

Bravo

AF:

0.0671

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Thrombocythemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.4

(source)

DANN

Benign

0.65

PhyloP100

-0.60

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over