6-18130687-T-C

Variant names:

• chr6-18130687-T-C
• rs1142345
• NM_000367.5:c.719A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (166 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1548 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: 4.69
• Publications: 405 publications found

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]

ENSG00000307971 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 12725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000367.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	NM_000367.5	MANE Select	c.719A>G	p.Tyr240Cys	missense	Exon 9 of 9	NP_000358.1
	TPMT	NM_001346817.1		c.719A>G	p.Tyr240Cys	missense	Exon 10 of 10	NP_001333746.1
	TPMT	NM_001346818.1		c.674A>G	p.Tyr225Cys	missense	Exon 8 of 8	NP_001333747.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	ENST00000309983.5	TSL:1 MANE Select	c.719A>G	p.Tyr240Cys	missense	Exon 9 of 9	ENSP00000312304.4
	ENSG00000307971	ENST00000830125.1		n.267+7581T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6567 AN: 152194 Hom.: 166 Cov.: 33

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

GnomAD2 exomes AF: 0.0367 AC: 9225 AN: 251130 AF XY: 0.0349

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 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

African (AFR) AF: 0.0553 AC: 1845 AN: 33360

American (AMR) AF: 0.0485 AC: 2168 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 410 AN: 26100

East Asian (EAS) AF: 0.0130 AC: 514 AN: 39624

South Asian (SAS) AF: 0.0167 AC: 1441 AN: 86114

European-Finnish (FIN) AF: 0.0302 AC: 1613 AN: 53406

Middle Eastern (MID) AF: 0.0104 AC: 48 AN: 4610

European-Non Finnish (NFE) AF: 0.0470 AC: 52125 AN: 1108834

Other (OTH) AF: 0.0359 AC: 2161 AN: 60154

GnomAD4 genome AF: 0.0432 AC: 6579 AN: 152312 Hom.: 166 Cov.: 33 AF XY: 0.0422 AC XY: 3145 AN XY: 74474

African (AFR) AF: 0.0550 AC: 2287 AN: 41560

American (AMR) AF: 0.0505 AC: 773 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5186

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4828

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0423 AC: 2876 AN: 68034

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0388 Hom.: 377

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:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

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).

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 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 v4.9

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
PhyloP100		4.7
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
Mutation Taster		=70/30	polymorphism (auto)

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

Other links and lift over

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