3-184376395-A-G

Variant names:

• chr3-184376395-A-G
• rs956732
• NM_000460.4:c.-136T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001290003.1(THPO):​c.285T>C​(p.Ser95Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,595,562 control chromosomes in the GnomAD database, including 219,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22606 hom., cov: 33)
  • Exomes 𝑓: 0.52 (196703 hom.)
• Consequence: THPO NM_001290003.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.565

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-184376395-A-G is Benign according to our data. Variant chr3-184376395-A-G is described in ClinVar as [Benign]. Clinvar id is 344376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184376395-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THPO	NM_000460.4	c.-136T>C		5_prime_UTR_variant	Exon 2 of 6	ENST00000647395.1	NP_000451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THPO	ENST00000647395.1	c.-136T>C		5_prime_UTR_variant	Exon 2 of 6		NM_000460.4	ENSP00000494504.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81972 AN: 151956 Hom.: 22585 Cov.: 33

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.519 AC: 749578 AN: 1443488 Hom.: 196703 Cov.: 41 AF XY: 0.515 AC XY: 369745 AN XY: 717472

Gnomad4 AFR exome AF: 0.604

Gnomad4 AMR exome AF: 0.611

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.430

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.529

GnomAD4 genome AF: 0.539 AC: 82043 AN: 152074 Hom.: 22606 Cov.: 33 AF XY: 0.529 AC XY: 39364 AN XY: 74350

Gnomad4 AFR AF: 0.602

Gnomad4 AMR AF: 0.613

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.423

Gnomad4 FIN AF: 0.357

Gnomad4 NFE AF: 0.529

Gnomad4 OTH AF: 0.584

Alfa AF: 0.544 Hom.: 21690

Bravo AF: 0.563

Asia WGS AF: 0.477 AC: 1663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocythemia 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs956732; hg19: chr3-184094183;