rs775627407

Variant names:

• chr3-184372521-C-A
• rs775627407
• NM_000460.4:c.1054G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-184372521-C-A
• chr3-184372521-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000460.4(THPO):​c.1054G>T​(p.Glu352*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THPO NM_000460.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00753 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THPO	NM_000460.4	MANE Select	c.1054G>T	p.Glu352*	stop_gained	Exon 6 of 6	NP_000451.1	P40225-1
	THPO	NM_001290003.1		c.1474G>T	p.Glu492*	stop_gained	Exon 7 of 7	NP_001276932.1	A0A3B3ITS0
	THPO	NM_001289998.1		c.1054G>T	p.Glu352*	stop_gained	Exon 7 of 7	NP_001276927.1	P40225-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THPO	ENST00000647395.1	MANE Select	c.1054G>T	p.Glu352*	stop_gained	Exon 6 of 6	ENSP00000494504.1	P40225-1
	THPO	ENST00000445696.6	TSL:1	c.1042G>T	p.Glu348*	stop_gained	Exon 6 of 6	ENSP00000410763.2	P40225-2
	THPO	ENST00000421442.2	TSL:1	c.*77G>T		3_prime_UTR	Exon 6 of 6	ENSP00000411704.2	F8W6L1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251494 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.60	D
PhyloP100		1.2
Vest4		0.50
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=107/93	polymorphism

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

Other links and lift over

dbSNP: rs775627407; hg19: chr3-184090309;