dbSNP rs4449636: 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:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000367.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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.

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.233+35C>T	intron	N/A	NP_000358.1	P51580
TPMT	NM_001346817.1		c.233+35C>T	intron	N/A	NP_001333746.1	P51580
TPMT	NM_001346818.1		c.233+35C>T	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.233+35C>T	intron	N/A	ENSP00000312304.4	P51580
TPMT	ENST00000864360.1		c.233+35C>T	intron	N/A	ENSP00000534419.1
TPMT	ENST00000864362.1		c.233+35C>T	intron	N/A	ENSP00000534421.1

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 v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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