chr3-184372454-C-T

Variant names:

• chr3-184372454-C-T
• rs78565404
• NM_000460.4:c.*59G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000460.4(THPO):​c.*59G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,604,796 control chromosomes in the GnomAD database, including 2,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (313 hom., cov: 33)
  • Exomes 𝑓: 0.057 (2613 hom.)
• Consequence: THPO NM_000460.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.600
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-184372454-C-T is Benign according to our data. Variant chr3-184372454-C-T is described in ClinVar as Benign. ClinVar VariationId is 344368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

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.*59G>A		3_prime_UTR	Exon 6 of 6	NP_000451.1	P40225-1
	THPO	NM_001290003.1		c.*59G>A		3_prime_UTR	Exon 7 of 7	NP_001276932.1	A0A3B3ITS0
	THPO	NM_001289998.1		c.*59G>A		3_prime_UTR	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.*59G>A		3_prime_UTR	Exon 6 of 6	ENSP00000494504.1	P40225-1
	THPO	ENST00000445696.6	TSL:1	c.*59G>A		3_prime_UTR	Exon 6 of 6	ENSP00000410763.2	P40225-2
	THPO	ENST00000421442.2	TSL:1	c.*144G>A		3_prime_UTR	Exon 6 of 6	ENSP00000411704.2	F8W6L1

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9592 AN: 152152 Hom.: 313 Cov.: 33

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0722

GnomAD4 exome AF: 0.0567 AC: 82360 AN: 1452526 Hom.: 2613 Cov.: 28 AF XY: 0.0574 AC XY: 41518 AN XY: 723220

African (AFR) AF: 0.0852 AC: 2837 AN: 33288

American (AMR) AF: 0.0685 AC: 3064 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2907 AN: 26082

East Asian (EAS) AF: 0.0218 AC: 865 AN: 39650

South Asian (SAS) AF: 0.0568 AC: 4882 AN: 85918

European-Finnish (FIN) AF: 0.0257 AC: 1370 AN: 53370

Middle Eastern (MID) AF: 0.0959 AC: 515 AN: 5372

European-Non Finnish (NFE) AF: 0.0563 AC: 62175 AN: 1104136

Other (OTH) AF: 0.0624 AC: 3745 AN: 60012

GnomAD4 genome AF: 0.0630 AC: 9594 AN: 152270 Hom.: 313 Cov.: 33 AF XY: 0.0617 AC XY: 4592 AN XY: 74450

African (AFR) AF: 0.0796 AC: 3308 AN: 41540

American (AMR) AF: 0.0699 AC: 1070 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3472

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5182

South Asian (SAS) AF: 0.0636 AC: 307 AN: 4830

European-Finnish (FIN) AF: 0.0219 AC: 232 AN: 10614

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0578 AC: 3932 AN: 68014

Other (OTH) AF: 0.0714 AC: 151 AN: 2114

Alfa AF: 0.0612 Hom.: 37

Bravo AF: 0.0671

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Thrombocythemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.4
DANN	Benign	0.65
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78565404; hg19: chr3-184090242;