Variant rs760797899 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_ModeratePP5_Moderate

The NM_000460.4(THPO):c.112C>T(p.Arg38Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

THPO
NM_000460.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.86

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

PP5

Variant 3-184375917-G-A is Pathogenic according to our data. Variant chr3-184375917-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520806.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THPO	NM_000460.4 linkuse as main transcript	c.112C>T	p.Arg38Cys	missense_variant	3/6	ENST00000647395.1	NP_000451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THPO	ENST00000647395.1 linkuse as main transcript	c.112C>T	p.Arg38Cys	missense_variant	3/6		NM_000460.4	ENSP00000494504	P2	P40225-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251156

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461446

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2019

- -

Amegakaryocytic thrombocytopenia, congenital, 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;T;.;.;.;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.91

.;D;.;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

M;M;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.4

D;.;.;D;D;.;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;.;.;D;D;.;.

Sift4G

Pathogenic

0.0010

D;.;.;D;D;.;.

Polyphen

1.0

D;D;.;D;D;.;D

Vest4

0.72

MutPred

0.70

Loss of methylation at R38 (P = 0.0409);Loss of methylation at R38 (P = 0.0409);.;Loss of methylation at R38 (P = 0.0409);Loss of methylation at R38 (P = 0.0409);.;Loss of methylation at R38 (P = 0.0409);

MVP

0.78

MPC

0.94

ClinPred

0.99

GERP RS

3.9

Varity_R

0.69

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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