Variant chr6-18133847-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000309983.5(TPMT):c.537G>T(p.Gln179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,611,974 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0065 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00064 ( 10 hom. )

Consequence

TPMT
ENST00000309983.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.41

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=0.01912865).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00646 (972/150470) while in subpopulation AFR AF= 0.022 (907/41134). AF 95% confidence interval is 0.0209. There are 15 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPMT	NM_000367.5 linkuse as main transcript	c.537G>T	p.Gln179His	missense_variant	7/9	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.537G>T	p.Gln179His	missense_variant	7/9	1	NM_000367.5	ENSP00000312304	P1

Frequencies

GnomAD3 genomes

AF:

0.00644

AC:

969

AN:

150438

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00312

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.00629

GnomAD3 exomes

AF:

0.00164

AC:

413

AN:

251380

Hom.:

AF XY:

0.00121

AC XY:

165

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0224

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000636

AC:

929

AN:

1461504

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

387

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.0229

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00646

AC:

972

AN:

150470

Hom.:

Cov.:

AF XY:

0.00632

AC XY:

463

AN XY:

73310

show subpopulations

Gnomad4 AFR

AF:

0.0220

Gnomad4 AMR

AF:

0.00311

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.00624

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00745

ESP6500AA

AF:

0.0195

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00193

AC:

234

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0020

DANN

Benign

0.58

DEOGEN2

Benign

0.15

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.57

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.85

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.60

REVEL

Benign

0.029

Sift

Benign

0.20

Sift4G

Benign

0.14

Polyphen

0.0070

Vest4

0.036

MutPred

0.27

Loss of catalytic residue at Q179 (P = 0.0927);

MVP

0.41

MPC

0.13

ClinPred

0.0060

GERP RS

-4.9

Varity_R

0.058

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over