Genetic Variant TPMT:p.Ala154Thr (chr6-18138997-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000367.5(TPMT):c.460G>A(p.Ala154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,611,706 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.026 ( 73 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1188 hom. )

Consequence

TPMT
NM_000367.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: -0.0930

Publications

333 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=0.008158416).

BP6

Variant 6-18138997-C-T is Benign according to our data. Variant chr6-18138997-C-T is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 37126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0258 (3933/152312) while in subpopulation AMR AF = 0.0385 (589/15298). AF 95% confidence interval is 0.037. There are 73 homozygotes in GnomAd4. There are 1887 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 73 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000367.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPMT	NM_000367.5	MANE Select	c.460G>A	p.Ala154Thr	missense	Exon 6 of 9	NP_000358.1	P51580
TPMT	NM_001346817.1		c.460G>A	p.Ala154Thr	missense	Exon 7 of 10	NP_001333746.1	P51580
TPMT	NM_001346818.1		c.460G>A	p.Ala154Thr	missense	Exon 6 of 8	NP_001333747.1	P51580

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPMT	ENST00000309983.5	TSL:1 MANE Select	c.460G>A	p.Ala154Thr	missense	Exon 6 of 9	ENSP00000312304.4	P51580
TPMT	ENST00000864360.1		c.460G>A	p.Ala154Thr	missense	Exon 7 of 10	ENSP00000534419.1
TPMT	ENST00000864362.1		c.460G>A	p.Ala154Thr	missense	Exon 6 of 9	ENSP00000534421.1

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3936

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00724

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0386

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00599

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0382

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0280

AC:

7048

AN:

251358

AF XY:

0.0266

show subpopulations

Gnomad AFR exome

AF:

0.00714

Gnomad AMR exome

AF:

0.0426

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0271

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0361

AC:

52612

AN:

1459394

Hom.:

1188

Cov.:

AF XY:

0.0349

AC XY:

25355

AN XY:

726138

show subpopulations

African (AFR)

AF:

0.00583

AC:

195

AN:

33474

American (AMR)

AF:

0.0430

AC:

1920

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0152

AC:

398

AN:

26124

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.00651

AC:

561

AN:

86232

European-Finnish (FIN)

AF:

0.0271

AC:

1446

AN:

53416

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0418

AC:

46369

AN:

1109656

Other (OTH)

AF:

0.0280

AC:

1688

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

2514

5028

7543

10057

12571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1726

3452

5178

6904

8630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0258

AC:

3933

AN:

152312

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1887

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00722

AC:

300

AN:

41578

American (AMR)

AF:

0.0385

AC:

589

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00600

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0265

AC:

281

AN:

10598

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0382

AC:

2598

AN:

68022

Other (OTH)

AF:

0.0255

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

207

414

622

829

1036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0326

Hom.:

124

Bravo

AF:

0.0266

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0400

AC:

154

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0376

AC:

323

ExAC

AF:

0.0275

AC:

3338

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0363

EpiControl

AF:

0.0357

ClinVar

ClinVar submissions

Significance:Benign/Likely benign; other

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

TPMT-related disorder (1)

Thiopurine S-methyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0082

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

3.7

PhyloP100

-0.093

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.023

Sift4G

Uncertain

0.0070

Polyphen

0.98

Vest4

0.14

MPC

0.49

ClinPred

0.097

GERP RS

-0.48

Varity_R

0.92

gMVP

0.72

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over