3-184372545-T-A

Variant names:

• chr3-184372545-T-A
• rs35794435
• NM_000460.4:c.1030A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000460.4(THPO):​c.1030A>T​(p.Thr344Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THPO NM_000460.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.449
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027775764).

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.1030A>T	p.Thr344Ser	missense	Exon 6 of 6	NP_000451.1	P40225-1
	THPO	NM_001290003.1		c.1450A>T	p.Thr484Ser	missense	Exon 7 of 7	NP_001276932.1	A0A3B3ITS0
	THPO	NM_001289998.1		c.1030A>T	p.Thr344Ser	missense	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.1030A>T	p.Thr344Ser	missense	Exon 6 of 6	ENSP00000494504.1	P40225-1
	THPO	ENST00000445696.6	TSL:1	c.1018A>T	p.Thr340Ser	missense	Exon 6 of 6	ENSP00000410763.2	P40225-2
	THPO	ENST00000421442.2	TSL:1	c.*53A>T		3_prime_UTR	Exon 6 of 6	ENSP00000411704.2	F8W6L1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.69
DANN	Benign	0.81
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.020
Sift	Benign	0.79	T
Sift4G	Benign	0.86	T
Polyphen		0.0010	B
Vest4		0.032
MutPred		0.074		Gain of phosphorylation at S346 (P = 0.0977)
MVP		0.17
MPC		0.19
ClinPred		0.34	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.11
Mutation Taster		=96/4	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: rs35794435; hg19: chr3-184090333;