NM_000367.5:c.719A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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

Publications

405 publications found

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:

ENSG00000307971 (HGNC:):

ENSG00000307971 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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
ENSG00000307971	ENST00000830125.1 link	n.267+7581T>C		intron_variant	Intron 1 of 2

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

GnomAD2 exomes

AF:

0.0367

AC:

9225

AN:

251130

AF XY:

0.0349

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 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

African (AFR)

AF:

0.0553

AC:

1845

AN:

33360

American (AMR)

AF:

0.0485

AC:

2168

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0157

AC:

410

AN:

26100

East Asian (EAS)

AF:

0.0130

AC:

514

AN:

39624

South Asian (SAS)

AF:

0.0167

AC:

1441

AN:

86114

European-Finnish (FIN)

AF:

0.0302

AC:

1613

AN:

53406

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

4610

European-Non Finnish (NFE)

AF:

0.0470

AC:

52125

AN:

1108834

Other (OTH)

AF:

0.0359

AC:

2161

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2672

5344

8015

10687

13359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0432

AC:

6579

AN:

152312

Hom.:

166

Cov.:

AF XY:

0.0422

AC XY:

3145

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0550

AC:

2287

AN:

41560

American (AMR)

AF:

0.0505

AC:

773

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.0137

AC:

AN:

5186

South Asian (SAS)

AF:

0.0188

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0293

AC:

311

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0423

AC:

2876

AN:

68034

Other (OTH)

AF:

0.0398

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

329

658

988

1317

1646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0388

Hom.:

377

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).

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 -

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) -

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

(source)

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

PhyloP100

4.7

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

Mutation Taster

=70/30

polymorphism (auto)

(source)

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

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NM_000367.5:c.719A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over