dbSNP rs12201199: 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:

Genome browser will be placed here

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.

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	Effect	Exon Rank	Protein	UniProt
TPMT	NM_000367.5	MANE Select	c.419+94T>A	intron	N/A	NP_000358.1	P51580
TPMT	NM_001346817.1		c.419+94T>A	intron	N/A	NP_001333746.1	P51580
TPMT	NM_001346818.1		c.419+94T>A	intron	N/A	NP_001333747.1	P51580

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPMT	ENST00000309983.5	TSL:1 MANE Select	c.419+94T>A	intron	N/A	ENSP00000312304.4	P51580
TPMT	ENST00000864360.1		c.419+94T>A	intron	N/A	ENSP00000534419.1
TPMT	ENST00000864362.1		c.419+94T>A	intron	N/A	ENSP00000534421.1

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over