6-18130687-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000367.5(TPMT):​c.719A>G​(p.Tyr240Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0428 in 1,609,224 control chromosomes in the GnomAD database, including 1,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y240S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.043 ( 166 hom., cov: 33)
Exomes 𝑓: 0.043 ( 1548 hom. )

Consequence

TPMT
NM_000367.5 missense

Scores

6
8
4

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:3O:2

Conservation

PhyloP100: 4.69
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.014096528).
BP6
Variant 6-18130687-T-C is Benign according to our data. Variant chr6-18130687-T-C is described in ClinVar as [Likely_benign, other]. Clinvar id is 12725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18130687-T-C is described in Lovd as [Benign]. Variant chr6-18130687-T-C is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPMTNM_000367.5 linkc.719A>G p.Tyr240Cys missense_variant Exon 9 of 9 ENST00000309983.5 NP_000358.1 P51580A0A024QZW0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TPMTENST00000309983.5 linkc.719A>G p.Tyr240Cys missense_variant Exon 9 of 9 1 NM_000367.5 ENSP00000312304.4 P51580

Frequencies

GnomAD3 genomes
AF:
0.0431
AC:
6567
AN:
152194
Hom.:
166
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0549
Gnomad AMI
AF:
0.0165
Gnomad AMR
AF:
0.0506
Gnomad ASJ
AF:
0.0190
Gnomad EAS
AF:
0.0137
Gnomad SAS
AF:
0.0186
Gnomad FIN
AF:
0.0293
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0423
Gnomad OTH
AF:
0.0402
GnomAD3 exomes
AF:
0.0367
AC:
9225
AN:
251130
Hom.:
232
AF XY:
0.0349
AC XY:
4743
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.0555
Gnomad AMR exome
AF:
0.0475
Gnomad ASJ exome
AF:
0.0130
Gnomad EAS exome
AF:
0.0146
Gnomad SAS exome
AF:
0.0178
Gnomad FIN exome
AF:
0.0306
Gnomad NFE exome
AF:
0.0429
Gnomad OTH exome
AF:
0.0337
GnomAD4 exome
AF:
0.0428
AC:
62325
AN:
1456912
Hom.:
1548
Cov.:
29
AF XY:
0.0415
AC XY:
30068
AN XY:
725030
show subpopulations
Gnomad4 AFR exome
AF:
0.0553
Gnomad4 AMR exome
AF:
0.0485
Gnomad4 ASJ exome
AF:
0.0157
Gnomad4 EAS exome
AF:
0.0130
Gnomad4 SAS exome
AF:
0.0167
Gnomad4 FIN exome
AF:
0.0302
Gnomad4 NFE exome
AF:
0.0470
Gnomad4 OTH exome
AF:
0.0359
GnomAD4 genome
AF:
0.0432
AC:
6579
AN:
152312
Hom.:
166
Cov.:
33
AF XY:
0.0422
AC XY:
3145
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0550
Gnomad4 AMR
AF:
0.0505
Gnomad4 ASJ
AF:
0.0190
Gnomad4 EAS
AF:
0.0137
Gnomad4 SAS
AF:
0.0188
Gnomad4 FIN
AF:
0.0293
Gnomad4 NFE
AF:
0.0423
Gnomad4 OTH
AF:
0.0398
Alfa
AF:
0.0409
Hom.:
248
Bravo
AF:
0.0457
TwinsUK
AF:
0.0507
AC:
188
ALSPAC
AF:
0.0457
AC:
176
ESP6500AA
AF:
0.0527
AC:
232
ESP6500EA
AF:
0.0417
AC:
358
ExAC
AF:
0.0366
AC:
4443
Asia WGS
AF:
0.0200
AC:
69
AN:
3476
EpiCase
AF:
0.0410
EpiControl
AF:
0.0399

ClinVar

Significance: Likely benign; other
Submissions summary: Benign:3Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3Other:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

May 12, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Also known as TPMT*3C, Y240C is one of the most common TPMT variants (Katara and Kuntal, 2015; Iu et al., 2017); Published functional studies demonstrate a damaging effect, as measurement of enzymatic activity showed only 10% activity for Y240C (Iu et al., 2017); Individuals who receive conventional thiopurine doses and carry at least one TPMT *3C allele are at risk to experience myelosuppression. Thiopurine dosing guidelines based on TPMT genotype are available (Relling et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed on 3.7% (10506/282534 alleles) from individuals in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27703193, 8561894, 15967990, 10591545, 25087612, 9695718, 18482735, 20970225, 26410243, 28462921, 8644731, 23422873, 31130284) -

Jul 21, 2015
Eurofins Ntd Llc (ga)
Significance: other
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TPMT: PM5, BS1, BS2 -

Thiopurine S-methyltransferase deficiency Other:1
Feb 01, 2006
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
Uncertain
0.43
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.85
T
MetaRNN
Benign
0.014
T
MetaSVM
Uncertain
0.21
D
MutationAssessor
Pathogenic
3.6
H
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-5.2
D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.028
D
Sift4G
Uncertain
0.015
D
Polyphen
1.0
D
Vest4
0.78
MPC
0.67
ClinPred
0.074
T
GERP RS
5.9
Varity_R
0.72
gMVP
0.87

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.

Other links and lift over

dbSNP: rs1142345; hg19: chr6-18130918; COSMIC: COSV59428256; API