Genetic Variant NM_000367.5:c.238G>C (chr6-18143724-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000367.5(TPMT):c.238G>C(p.Ala80Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,984 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 9 hom. )

Consequence

TPMT
NM_000367.5 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 2.18

Publications

241 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.124863535).

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5 link	c.238G>C	p.Ala80Pro	missense_variant	Exon 4 of 9	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5 link	c.238G>C	p.Ala80Pro	missense_variant	Exon 4 of 9	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1 link	n.268-5764C>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00174

AC:

437

AN:

251094

AF XY:

0.00188

show subpopulations

Gnomad AFR exome

AF:

0.000496

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00239

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00215

AC:

3142

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1510

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33476

American (AMR)

AF:

0.00376

AC:

168

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00199

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00249

AC:

2769

AN:

1111956

Other (OTH)

AF:

0.00209

AC:

126

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

166

332

499

665

831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00203

AC:

309

AN:

152254

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

166

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41552

American (AMR)

AF:

0.00707

AC:

108

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

68024

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00238

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00137

AC:

166

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00255

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thiopurine S-methyltransferase deficiency

Other:1

Feb 01, 1999

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.068

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.7

PhyloP100

2.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.85

Sift

Uncertain

0.016

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.85

MVP

0.95

MPC

0.68

ClinPred

0.10

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.92

Mutation Taster

=41/59

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over