6-18143538-A-G

Variant names:

• chr6-18143538-A-G
• rs2518463
• NM_000367.5:c.366+58T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 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.366+58T>C		intron	N/A	NP_000358.1
	TPMT	NM_001346817.1		c.366+58T>C		intron	N/A	NP_001333746.1
	TPMT	NM_001346818.1		c.366+58T>C		intron	N/A	NP_001333747.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	ENST00000309983.5	TSL:1 MANE Select	c.366+58T>C		intron	N/A	ENSP00000312304.4
	TPMT	ENST00000864360.1		c.366+58T>C		intron	N/A	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.366+58T>C		intron	N/A	ENSP00000534421.1

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

African (AFR) AF: 0.700 AC: 23280 AN: 33258

American (AMR) AF: 0.572 AC: 25566 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 12472 AN: 26048

East Asian (EAS) AF: 0.400 AC: 15808 AN: 39538

South Asian (SAS) AF: 0.440 AC: 37739 AN: 85768

European-Finnish (FIN) AF: 0.536 AC: 28236 AN: 52640

Middle Eastern (MID) AF: 0.495 AC: 2043 AN: 4128

European-Non Finnish (NFE) AF: 0.541 AC: 598521 AN: 1106788

Other (OTH) AF: 0.525 AC: 31484 AN: 59992

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

African (AFR) AF: 0.693 AC: 28758 AN: 41468

American (AMR) AF: 0.563 AC: 8594 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1643 AN: 3470

East Asian (EAS) AF: 0.386 AC: 1996 AN: 5176

South Asian (SAS) AF: 0.437 AC: 2106 AN: 4820

European-Finnish (FIN) AF: 0.527 AC: 5571 AN: 10570

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.536 AC: 36429 AN: 67982

Other (OTH) AF: 0.554 AC: 1170 AN: 2112

Alfa AF: 0.543 Hom.: 91342

Bravo AF: 0.583

Asia WGS AF: 0.452 AC: 1575 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.92
DANN	Benign	0.45
PhyloP100		-1.0
Mutation Taster		=100/0	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: rs2518463; hg19: chr6-18143769; COSMIC: COSV59429083;