rs2842949

chr6-18133790-C-A

Variant summary

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

The NM_000367.5(TPMT):c.580+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 1,548,776 control chromosomes in the GnomAD database, including 378,858 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 0.62 (29317 hom., cov: 30)
  • Exomes 𝑓: 0.70 (349541 hom.)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPMT	NM_000367.5	c.580+14G>T		intron_variant		ENST00000309983.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPMT	ENST00000309983.5	c.580+14G>T		intron_variant		1	NM_000367.5	P1

Frequencies

GnomAD3 genomes AF: 0.620 AC: 90982 AN: 146846 Hom.: 29327 Cov.: 30

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.641

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.630

GnomAD3 exomes AF: 0.669 AC: 143254 AN: 214212 Hom.: 48355 AF XY: 0.672 AC XY: 78222 AN XY: 116400

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.685

Gnomad EAS exome AF: 0.757

Gnomad SAS exome AF: 0.613

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.704 AC: 987431 AN: 1401876 Hom.: 349541 Cov.: 29 AF XY: 0.703 AC XY: 490966 AN XY: 698166

Gnomad4 AFR exome AF: 0.362

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.737

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.697

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.619 AC: 90972 AN: 146900 Hom.: 29317 Cov.: 30 AF XY: 0.617 AC XY: 44118 AN XY: 71478

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.689

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.608

Gnomad4 FIN AF: 0.685

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.630

Alfa AF: 0.637 Hom.: 3112

Bravo AF: 0.599

Asia WGS AF: 0.637 AC: 2143 AN: 3368

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.6
Dann	Benign	0.26

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: rs2842949; hg19: chr6-18134021; COSMIC: COSV59428486;