rs35794435

chr3-184372545-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000460.4(THPO):c.1030A>G(p.Thr344Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,244 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T344T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (11 hom.)
• Consequence: THPO NM_000460.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.449

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 (MetaRNN=0.0029999018).
• BP6: Variant 3-184372545-T-C is Benign according to our data. Variant chr3-184372545-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256211.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 = 0.00658 (996/151368) while in subpopulation AFR AF= 0.0226 (929/41184). AF 95% confidence interval is 0.0214. There are 14 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THPO	NM_000460.4	c.1030A>G	p.Thr344Ala	missense_variant	6/6	ENST00000647395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THPO	ENST00000647395.1	c.1030A>G	p.Thr344Ala	missense_variant	6/6		NM_000460.4	P2

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 983 AN: 151252 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00771

GnomAD3 exomes AF: 0.00167 AC: 419 AN: 251488 Hom.: 6 AF XY: 0.00123 AC XY: 167 AN XY: 135918

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000727 AC: 1063 AN: 1461876 Hom.: 11 Cov.: 34 AF XY: 0.000638 AC XY: 464 AN XY: 727232

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00658 AC: 996 AN: 151368 Hom.: 14 Cov.: 32 AF XY: 0.00637 AC XY: 471 AN XY: 73928

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00250

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00763

Alfa AF: 0.00164 Hom.: 5

Bravo AF: 0.00697

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

Thrombocythemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.4
Dann	Benign	0.63
DEOGEN2	Benign	0.25	T;T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0030	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.62	N;.;.;N;.
REVEL	Benign	0.014
Sift	Benign	0.45	T;.;.;T;.
Sift4G	Benign	0.74	T;.;.;T;.
Polyphen		0.015	B;B;.;B;.
Vest4		0.041
MVP		0.19
MPC		0.20
ClinPred		0.0070	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs35794435; hg19: chr3-184090333;