Genetic Variant TPMT:c.419+94T>A (chr6-18139571-A-T) – 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.419+94T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0822 in 987,832 control chromosomes in the GnomAD database, including 7,519 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 0.16 ( 3912 hom., cov: 32)

Exomes 𝑓: 0.068 ( 3607 hom. )

Consequence

TPMT
NM_000367.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.77

Publications

38 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=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5 link	c.419+94T>A		intron_variant	Intron 5 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.419+94T>A		intron_variant	Intron 5 of 8	1	NM_000367.5	ENSP00000312304.4		P51580
ENSG00000307971	ENST00000830125.1 link	n.268-9917A>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.160

AC:

24347

AN:

151974

Hom.:

3892

Cov.:

show subpopulations

Gnomad AFR

AF:

0.418

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.0550

Gnomad MID

AF:

0.0796

Gnomad NFE

AF:

0.0619

Gnomad OTH

AF:

0.134

GnomAD4 exome

AF:

0.0680

AC:

56828

AN:

835742

Hom.:

3607

AF XY:

0.0638

AC XY:

28083

AN XY:

440152

show subpopulations

African (AFR)

AF:

0.430

AC:

8835

AN:

20536

American (AMR)

AF:

0.0882

AC:

3417

AN:

38720

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

518

AN:

21364

East Asian (EAS)

AF:

0.0133

AC:

489

AN:

36782

South Asian (SAS)

AF:

0.0215

AC:

1502

AN:

69926

European-Finnish (FIN)

AF:

0.0597

AC:

3145

AN:

52664

Middle Eastern (MID)

AF:

0.0385

AC:

154

AN:

4000

European-Non Finnish (NFE)

AF:

0.0645

AC:

35637

AN:

552310

Other (OTH)

AF:

0.0794

AC:

3131

AN:

39440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2450

4900

7349

9799

12249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<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:

0.161

AC:

24416

AN:

152090

Hom.:

3912

Cov.:

AF XY:

0.156

AC XY:

11590

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.419

AC:

17341

AN:

41408

American (AMR)

AF:

0.110

AC:

1683

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3468

East Asian (EAS)

AF:

0.0141

AC:

AN:

5180

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4824

European-Finnish (FIN)

AF:

0.0550

AC:

583

AN:

10606

Middle Eastern (MID)

AF:

0.0719

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0619

AC:

4208

AN:

68016

Other (OTH)

AF:

0.133

AC:

279

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

839

1677

2516

3354

4193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.116

Hom.:

293

Bravo

AF:

0.178

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.0050

(source)

DANN

Benign

0.48

PhyloP100

-3.8

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