6-18138997-C-T

Position:

chr6-18138997-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000309983.5(TPMT):c.460G>A(p.Ala154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,611,706 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.026 ( 73 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1188 hom. )

Consequence

TPMT
ENST00000309983.5 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: -0.0930

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008158416).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0258 (3933/152312) while in subpopulation AMR AF= 0.0385 (589/15298). AF 95% confidence interval is 0.037. There are 73 homozygotes in gnomad4. There are 1887 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPMT	NM_000367.5 linkuse as main transcript	c.460G>A	p.Ala154Thr	missense_variant	6/9	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5 linkuse as main transcript	c.460G>A	p.Ala154Thr	missense_variant	6/9	1	NM_000367.5	ENSP00000312304	P1

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3936

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00724

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0386

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00599

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0382

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0280

AC:

7048

AN:

251358

Hom.:

160

AF XY:

0.0266

AC XY:

3619

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00714

Gnomad AMR exome

AF:

0.0426

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00683

Gnomad FIN exome

AF:

0.0271

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0361

AC:

52612

AN:

1459394

Hom.:

1188

Cov.:

AF XY:

0.0349

AC XY:

25355

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.00583

Gnomad4 AMR exome

AF:

0.0430

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00651

Gnomad4 FIN exome

AF:

0.0271

Gnomad4 NFE exome

AF:

0.0418

Gnomad4 OTH exome

AF:

0.0280

GnomAD4 genome

AF:

0.0258

AC:

3933

AN:

152312

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1887

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00722

Gnomad4 AMR

AF:

0.0385

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00600

Gnomad4 FIN

AF:

0.0265

Gnomad4 NFE

AF:

0.0382

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0335

Hom.:

104

Bravo

AF:

0.0266

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0400

AC:

154

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0376

AC:

323

ExAC

AF:

0.0275

AC:

3338

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0363

EpiControl

AF:

0.0357

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TPMT: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TPMT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Thiopurine S-methyltransferase deficiency

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Feb 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0082

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.023

Sift4G

Uncertain

0.0070

Polyphen

0.98

Vest4

0.14

MPC

0.49

ClinPred

0.097

GERP RS

-0.48

Varity_R

0.92

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over