rs55827759

chr3-184373595-T-TGGAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000460.4(THPO):c.229-14_229-13insTTCC variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.89

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 113 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THPO	NM_000460.4	c.229-14_229-13insTTCC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000647395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THPO	ENST00000647395.1	c.229-14_229-13insTTCC		splice_polypyrimidine_tract_variant, intron_variant			NM_000460.4	P2

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

GnomAD3 exomes AF: 0.0300 AC: 7520 AN: 250498 Hom.: 134 AF XY: 0.0302 AC XY: 4096 AN XY: 135454

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 SAS exome AF: 0.0244

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

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0500

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0366

Gnomad4 OTH exome AF: 0.0353

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

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0366 Hom.: 20

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Thrombocythemia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55827759; hg19: chr3-184091383;