rs12201199

Positions:

• chr6-18139571-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000309983.5(TPMT):​c.419+94T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0822 in 987,832 control chromosomes in the GnomAD database, including 7,519 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (3912 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3607 hom.)
• Consequence: TPMT ENST00000309983.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.77

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPMT	NM_000367.5	c.419+94T>A		intron_variant		ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.419+94T>A		intron_variant		1	NM_000367.5	ENSP00000312304	P1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24347 AN: 151974 Hom.: 3892 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0550

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.134

GnomAD4 exome AF: 0.0680 AC: 56828 AN: 835742 Hom.: 3607 AF XY: 0.0638 AC XY: 28083 AN XY: 440152

Gnomad4 AFR exome AF: 0.430

Gnomad4 AMR exome AF: 0.0882

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.0133

Gnomad4 SAS exome AF: 0.0215

Gnomad4 FIN exome AF: 0.0597

Gnomad4 NFE exome AF: 0.0645

Gnomad4 OTH exome AF: 0.0794

GnomAD4 genome AF: 0.161 AC: 24416 AN: 152090 Hom.: 3912 Cov.: 32 AF XY: 0.156 AC XY: 11590 AN XY: 74366

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0550

Gnomad4 NFE AF: 0.0619

Gnomad4 OTH AF: 0.133

Alfa AF: 0.116 Hom.: 293

Bravo AF: 0.178

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.0050
DANN	Benign	0.48

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

Other links and lift over

dbSNP: rs12201199; hg19: chr6-18139802;