chr3-184372545-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000460.4(THPO):c.1030A>G(p.Thr344Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,244 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0066 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 11 hom. )

Consequence

THPO
NM_000460.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.449

Publications

5 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 (MetaRNN=0.0029999018).

BP6

Variant 3-184372545-T-C is Benign according to our data. Variant chr3-184372545-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00658 (996/151368) while in subpopulation AFR AF = 0.0226 (929/41184). AF 95% confidence interval is 0.0214. There are 14 homozygotes in GnomAd4. There are 471 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THPO	NM_000460.4 link	c.1030A>G	p.Thr344Ala	missense_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.1030A>G	p.Thr344Ala	missense_variant	Exon 6 of 6		NM_000460.4	ENSP00000494504.1		P40225-1

Frequencies

GnomAD3 genomes

AF:

0.00650

AC:

983

AN:

151252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00250

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00771

GnomAD2 exomes

AF:

0.00167

AC:

419

AN:

251488

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.0227

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000727

AC:

1063

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000638

AC XY:

464

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0240

AC:

804

AN:

33480

American (AMR)

AF:

0.000805

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000971

AC:

108

AN:

1112004

Other (OTH)

AF:

0.00157

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00658

AC:

996

AN:

151368

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

471

AN XY:

73928

show subpopulations

African (AFR)

AF:

0.0226

AC:

929

AN:

41184

American (AMR)

AF:

0.00250

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67828

Other (OTH)

AF:

0.00763

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00313

Hom.:

Bravo

AF:

0.00697

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00221

AC:

268

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 19, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jun 01, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thrombocythemia 1

Benign:1

Jan 12, 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

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.4

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.25

T;T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.25

.;T;.;T;T

MetaRNN

Benign

0.0030

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.;.;.

PhyloP100

-0.45

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.62

N;.;.;N;.

REVEL

Benign

0.014

Sift

Benign

0.45

T;.;.;T;.

Sift4G

Benign

0.74

T;.;.;T;.

Polyphen

0.015

B;B;.;B;.

Vest4

0.041

MVP

0.19

MPC

0.20

ClinPred

0.0070

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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