3-184378790-A-G

Position:

• chr3-184378790-A-G

Variant summary

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

The ENST00000691896.2(ENSG00000289500):​n.559A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 984,546 control chromosomes in the GnomAD database, including 122,432 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 0.49 (18937 hom., cov: 32)
  • Exomes 𝑓: 0.50 (103495 hom.)
• Consequence: ENST00000691896.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37

Genes affected

(HGNC:):

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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THPO	NM_001289998.1	c.-448-413T>C		intron_variant
THPO	NM_001290003.1	c.-28-413T>C		intron_variant
THPO	NM_001290022.1	c.-448-413T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000691896.2	n.559A>G		non_coding_transcript_exon_variant	1/1
THPO	ENST00000645603.2	c.-28-413T>C		intron_variant				A2
THPO	ENST00000649095.1	c.-28-413T>C		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75118 AN: 151918 Hom.: 18916 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.541

GnomAD4 exome AF: 0.497 AC: 414169 AN: 832510 Hom.: 103495 Cov.: 29 AF XY: 0.497 AC XY: 190935 AN XY: 384464

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.635

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.460

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.497

Gnomad4 OTH exome AF: 0.511

GnomAD4 genome AF: 0.495 AC: 75188 AN: 152036 Hom.: 18937 Cov.: 32 AF XY: 0.489 AC XY: 36330 AN XY: 74328

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.488

Gnomad4 OTH AF: 0.540

Alfa AF: 0.501 Hom.: 25960

Bravo AF: 0.515

Asia WGS AF: 0.453 AC: 1579 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.16
DANN	Benign	0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs885838; hg19: chr3-184096578;