chr3-184379297-A-G

Variant names:

• chr3-184379297-A-G
• rs2855306
• ENST00000691896.3:n.1243A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000691896.3(ENSG00000289500):​n.1243A>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 0.281 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: ENSG00000289500 ENST00000691896.3 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 7 publications found

Genes affected

ENSG00000289500 (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]

THPO Gene-Disease associations (from GenCC):

• thrombocythemia 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
THPO	NM_001290003.1	c.-29+294T>C		intron_variant	Intron 1 of 6		NP_001276932.1
THPO	NM_001289998.1	c.-449+294T>C		intron_variant	Intron 1 of 6		NP_001276927.1
THPO	NM_001290028.1	c.-146+294T>C		intron_variant	Intron 1 of 5		NP_001276957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289500	ENST00000691896.3	n.1243A>G		non_coding_transcript_exon_variant	Exon 1 of 1
THPO	ENST00000645603.2	c.-28-920T>C		intron_variant	Intron 2 of 7			ENSP00000494281.2
THPO	ENST00000649095.1	c.-29+294T>C		intron_variant	Intron 1 of 6			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

African (AFR) AF: 0.254 AC: 10506 AN: 41350

American (AMR) AF: 0.269 AC: 4108 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1501 AN: 3468

East Asian (EAS) AF: 0.0566 AC: 292 AN: 5158

South Asian (SAS) AF: 0.210 AC: 1008 AN: 4798

European-Finnish (FIN) AF: 0.188 AC: 1985 AN: 10582

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22028 AN: 67922

Other (OTH) AF: 0.336 AC: 705 AN: 2098

Alfa AF: 0.325 Hom.: 9909

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
PhyloP100		1.6
PromoterAI		0.00080	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2855306; hg19: chr3-184097085;