Genetic Variant TPMT:c.233+35C>T (chr6-18147788-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000367.5(TPMT):c.233+35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,570,128 control chromosomes in the GnomAD database, including 228,187 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.57 ( 25351 hom., cov: 33)

Exomes 𝑓: 0.53 ( 202836 hom. )

Consequence

TPMT
NM_000367.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00500

Publications

14 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5 link	c.233+35C>T		intron_variant	Intron 3 of 8	ENST00000309983.5	NP_000358.1	P51580A0A024QZW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5 link	c.233+35C>T		intron_variant	Intron 3 of 8	1	NM_000367.5	ENSP00000312304.4		P51580
ENSG00000307971	ENST00000830125.1 link	n.268-1700G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.571

AC:

86740

AN:

151910

Hom.:

25310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.692

Gnomad AMI

AF:

0.648

Gnomad AMR

AF:

0.563

Gnomad ASJ

AF:

0.473

Gnomad EAS

AF:

0.373

Gnomad SAS

AF:

0.435

Gnomad FIN

AF:

0.529

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.535

Gnomad OTH

AF:

0.554

GnomAD2 exomes

AF:

0.519

AC:

129684

AN:

249814

AF XY:

0.512

show subpopulations

Gnomad AFR exome

AF:

0.697

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.477

Gnomad EAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.517

GnomAD4 exome

AF:

0.533

AC:

756083

AN:

1418100

Hom.:

202836

Cov.:

AF XY:

0.528

AC XY:

373929

AN XY:

707994

show subpopulations

African (AFR)

AF:

0.698

AC:

22777

AN:

32642

American (AMR)

AF:

0.572

AC:

25435

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.480

AC:

12386

AN:

25816

East Asian (EAS)

AF:

0.385

AC:

15163

AN:

39392

South Asian (SAS)

AF:

0.439

AC:

37243

AN:

84820

European-Finnish (FIN)

AF:

0.536

AC:

28596

AN:

53360

Middle Eastern (MID)

AF:

0.503

AC:

2385

AN:

4740

European-Non Finnish (NFE)

AF:

0.541

AC:

581205

AN:

1073966

Other (OTH)

AF:

0.525

AC:

30893

AN:

58878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

16991

33982

50974

67965

84956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16364

32728

49092

65456

81820

<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:

0.571

AC:

86839

AN:

152028

Hom.:

25351

Cov.:

AF XY:

0.568

AC XY:

42214

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.692

AC:

28703

AN:

41468

American (AMR)

AF:

0.563

AC:

8587

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.473

AC:

1642

AN:

3470

East Asian (EAS)

AF:

0.373

AC:

1931

AN:

5172

South Asian (SAS)

AF:

0.437

AC:

2106

AN:

4824

European-Finnish (FIN)

AF:

0.529

AC:

5577

AN:

10542

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.535

AC:

36382

AN:

67978

Other (OTH)

AF:

0.553

AC:

1166

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1905

3810

5716

7621

9526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.546

Hom.:

60919

Bravo

AF:

0.581

Asia WGS

AF:

0.448

AC:

1559

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.8

(source)

DANN

Benign

0.61

PhyloP100

0.0050

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over