chr3-184379297-A-G

Position:

• chr3-184379297-A-G

Variant summary

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

The NM_001290003.1(THPO):​c.-29+294T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 151,838 control chromosomes in the GnomAD database, including 6,378 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 0.28 (6378 hom., cov: 31)
• Consequence: THPO NM_001290003.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THPO	NM_001290003.1	c.-29+294T>C		intron_variant			NP_001276932.1
THPO	NM_001289998.1	c.-449+294T>C		intron_variant			NP_001276927.1
THPO	NM_001290028.1	c.-146+294T>C		intron_variant			NP_001276957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THPO	ENST00000645603.2	c.-28-920T>C		intron_variant				ENSP00000494281.2
THPO	ENST00000649095.1	c.-29+294T>C		intron_variant				ENSP00000497904.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42576 AN: 151722 Hom.: 6374 Cov.: 31

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.0567

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.281 AC: 42599 AN: 151838 Hom.: 6378 Cov.: 31 AF XY: 0.272 AC XY: 20219 AN XY: 74222

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.0566

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.336

Alfa AF: 0.327 Hom.: 8411

Bravo AF: 0.286

Asia WGS AF: 0.167 AC: 583 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.81

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2855306; hg19: chr3-184097085;