Genetic Variant TPMT:p.Ile112Thr (chr6-18143627-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000367.5(TPMT):c.335T>C(p.Ile112Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I112N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPMT
NM_000367.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.52

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3232016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5 link	c.335T>C	p.Ile112Thr	missense_variant	Exon 4 of 9	ENST00000309983.5	NP_000358.1	P51580A0A024QZW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5 link	c.335T>C	p.Ile112Thr	missense_variant	Exon 4 of 9	1	NM_000367.5	ENSP00000312304.4		P51580
ENSG00000307971	ENST00000830125.1 link	n.268-5861A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5084

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.044

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.6

PhyloP100

6.5

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.28

Sift

Benign

0.14

Sift4G

Benign

0.20

Polyphen

0.75

Vest4

0.23

MutPred

0.59

Gain of glycosylation at I112 (P = 0.0095);

MVP

0.86

MPC

0.27

ClinPred

0.87

GERP RS

4.1

Varity_R

0.35

gMVP

0.51

Mutation Taster

=82/18

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over