6-18130687-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000367.5(TPMT):c.719A>G(p.Tyr240Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0428 in 1,609,224 control chromosomes in the GnomAD database, including 1,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y240S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.043 ( 166 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1548 hom. )

Consequence

TPMT
NM_000367.5 missense

Scores

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:3O:2

Conservation

PhyloP100: 4.69

Variant links:

Genes affected

TPMT (HGNC:12014): (thiopurine S-methyltransferase) This gene encodes the enzyme that metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals, causing thiopurine S-methyltransferase deficiency. Related pseudogenes have been identified on chromosomes 3, 18 and X. [provided by RefSeq, Aug 2014]

TPMT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014096528).

BP6

Variant 6-18130687-T-C is Benign according to our data. Variant chr6-18130687-T-C is described in ClinVar as [Likely_benign, other]. Clinvar id is 12725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18130687-T-C is described in Lovd as [Benign]. Variant chr6-18130687-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5 link	c.719A>G	p.Tyr240Cys	missense_variant	Exon 9 of 9	ENST00000309983.5	NP_000358.1	P51580A0A024QZW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5 link	c.719A>G	p.Tyr240Cys	missense_variant	Exon 9 of 9	1	NM_000367.5	ENSP00000312304.4		P51580

Frequencies

GnomAD3 genomes

AF:

0.0431

AC:

6567

AN:

152194

Hom.:

166

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.0506

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0367

AC:

9225

AN:

251130

Hom.:

232

AF XY:

0.0349

AC XY:

4743

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0555

Gnomad AMR exome

AF:

0.0475

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.0146

Gnomad SAS exome

AF:

0.0178

Gnomad FIN exome

AF:

0.0306

Gnomad NFE exome

AF:

0.0429

Gnomad OTH exome

AF:

0.0337

GnomAD4 exome

AF:

0.0428

AC:

62325

AN:

1456912

Hom.:

1548

Cov.:

AF XY:

0.0415

AC XY:

30068

AN XY:

725030

show subpopulations

Gnomad4 AFR exome

AF:

0.0553

Gnomad4 AMR exome

AF:

0.0485

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.0130

Gnomad4 SAS exome

AF:

0.0167

Gnomad4 FIN exome

AF:

0.0302

Gnomad4 NFE exome

AF:

0.0470

Gnomad4 OTH exome

AF:

0.0359

GnomAD4 genome

AF:

0.0432

AC:

6579

AN:

152312

Hom.:

166

Cov.:

AF XY:

0.0422

AC XY:

3145

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0550

Gnomad4 AMR

AF:

0.0505

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.0137

Gnomad4 SAS

AF:

0.0188

Gnomad4 FIN

AF:

0.0293

Gnomad4 NFE

AF:

0.0423

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0409

Hom.:

248

Bravo

AF:

0.0457

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0457

AC:

176

ESP6500AA

AF:

0.0527

AC:

232

ESP6500EA

AF:

0.0417

AC:

358

ExAC

AF:

0.0366

AC:

4443

Asia WGS

AF:

0.0200

AC:

AN:

3476

EpiCase

AF:

0.0410

EpiControl

AF:

0.0399

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:3Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Jul 21, 2015

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

May 12, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as TPMT*3C, Y240C is one of the most common TPMT variants (Katara and Kuntal, 2015; Iu et al., 2017); Published functional studies demonstrate a damaging effect, as measurement of enzymatic activity showed only 10% activity for Y240C (Iu et al., 2017); Individuals who receive conventional thiopurine doses and carry at least one TPMT *3C allele are at risk to experience myelosuppression. Thiopurine dosing guidelines based on TPMT genotype are available (Relling et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed on 3.7% (10506/282534 alleles) from individuals in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27703193, 8561894, 15967990, 10591545, 25087612, 9695718, 18482735, 20970225, 26410243, 28462921, 8644731, 23422873, 31130284) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPMT: PM5, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thiopurine S-methyltransferase deficiency

Other:1

Feb 01, 2006

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.70

Sift

Uncertain

0.028

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.78

MPC

0.67

ClinPred

0.074

GERP RS

5.9

Varity_R

0.72

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over