rs2518463

Positions:

• chr6-18143538-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000367.5(TPMT):​c.366+58T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,604,884 control chromosomes in the GnomAD database, including 233,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.57 (25445 hom., cov: 32)
  • Exomes 𝑓: 0.53 (208206 hom.)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-18143538-A-G is Benign according to our data. Variant chr6-18143538-A-G is described in Lovd as [Benign]. Variant chr6-18143538-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPMT	NM_000367.5	c.366+58T>C		intron_variant		ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.366+58T>C		intron_variant		1	NM_000367.5	ENSP00000312304.4

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86915 AN: 151950 Hom.: 25405 Cov.: 32

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.555

GnomAD4 exome AF: 0.534 AC: 775149 AN: 1452818 Hom.: 208206 AF XY: 0.529 AC XY: 382184 AN XY: 723060

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.400

Gnomad4 SAS exome AF: 0.440

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.525

GnomAD4 genome AF: 0.572 AC: 87012 AN: 152066 Hom.: 25445 Cov.: 32 AF XY: 0.569 AC XY: 42299 AN XY: 74306

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.563

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.527

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.554

Alfa AF: 0.536 Hom.: 37313

Bravo AF: 0.583

Asia WGS AF: 0.452 AC: 1575 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.92
DANN	Benign	0.45

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: rs2518463; hg19: chr6-18143769; COSMIC: COSV59429083;