rs10513797

Positions:

• chr3-184374693-G-A
• chr3-184374693-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000460.4(THPO):​c.228+822C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,266 control chromosomes in the GnomAD database, including 1,454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1454 hom., cov: 33)
• Consequence: THPO NM_000460.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.954

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THPO	NM_000460.4	c.228+822C>T		intron_variant		ENST00000647395.1	NP_000451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THPO	ENST00000647395.1	c.228+822C>T		intron_variant			NM_000460.4	ENSP00000494504	P2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19109 AN: 152148 Hom.: 1449 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.0650

Gnomad FIN AF: 0.0669

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.121

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.126 AC: 19137 AN: 152266 Hom.: 1454 Cov.: 33 AF XY: 0.123 AC XY: 9194 AN XY: 74450

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0925

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.0648

Gnomad4 FIN AF: 0.0669

Gnomad4 NFE AF: 0.0836

Gnomad4 OTH AF: 0.120

Alfa AF: 0.0867 Hom.: 946

Bravo AF: 0.136

Asia WGS AF: 0.102 AC: 356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.7
DANN	Benign	0.88

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

LitVar

Other links and lift over

dbSNP: rs10513797; hg19: chr3-184092481;