rs55827759

Variant names:

• chr3-184373595-T-TGGAA
• rs55827759
• NM_000460.4:c.229-17_229-14dupTTCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000460.4(THPO):​c.229-17_229-14dupTTCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,613,588 control chromosomes in the GnomAD database, including 1,094 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (113 hom., cov: 32)
  • Exomes 𝑓: 0.034 (981 hom.)
• Consequence: THPO NM_000460.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.89
• Publications: 1 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: 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 -16 ACMG points.

• BP6: Variant 3-184373595-T-TGGAA is Benign according to our data. Variant chr3-184373595-T-TGGAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0351 (5341/152076) while in subpopulation AFR AF = 0.0438 (1816/41476). AF 95% confidence interval is 0.0421. There are 113 homozygotes in GnomAd4. There are 2590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 113 AD,AR gene

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.229-17_229-14dupTTCC		intron	N/A	NP_000451.1
	THPO	NM_001290003.1		c.649-17_649-14dupTTCC		intron	N/A	NP_001276932.1
	THPO	NM_001289998.1		c.229-17_229-14dupTTCC		intron	N/A	NP_001276927.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THPO	ENST00000647395.1	MANE Select	c.229-14_229-13insTTCC		intron	N/A	ENSP00000494504.1
	THPO	ENST00000445696.6	TSL:1	c.229-14_229-13insTTCC		intron	N/A	ENSP00000410763.2
	THPO	ENST00000421442.2	TSL:1	c.229-14_229-13insTTCC		intron	N/A	ENSP00000411704.2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5327 AN: 151958 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0300 AC: 7520 AN: 250498 AF XY: 0.0302

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0525

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0367

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0344 AC: 50227 AN: 1461512 Hom.: 981 Cov.: 33 AF XY: 0.0342 AC XY: 24851 AN XY: 727064

African (AFR) AF: 0.0470 AC: 1572 AN: 33468

American (AMR) AF: 0.0192 AC: 859 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 1306 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.0242 AC: 2089 AN: 86194

European-Finnish (FIN) AF: 0.0261 AC: 1390 AN: 53312

Middle Eastern (MID) AF: 0.0330 AC: 190 AN: 5754

European-Non Finnish (NFE) AF: 0.0366 AC: 40683 AN: 1111882

Other (OTH) AF: 0.0353 AC: 2134 AN: 60382

GnomAD4 genome AF: 0.0351 AC: 5341 AN: 152076 Hom.: 113 Cov.: 32 AF XY: 0.0348 AC XY: 2590 AN XY: 74370

African (AFR) AF: 0.0438 AC: 1816 AN: 41476

American (AMR) AF: 0.0275 AC: 420 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5148

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4820

European-Finnish (FIN) AF: 0.0261 AC: 276 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2441 AN: 67974

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0366 Hom.: 20

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
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: rs55827759; hg19: chr3-184091383;