rs9367980

chr6-18131233-C-Achr6-18131233-C-Gchr6-18131233-C-T

Variant summary

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

The NM_000367.5(TPMT):c.626-453G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 152,054 control chromosomes in the GnomAD database, including 29,845 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 0.61 (29845 hom., cov: 33)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPMT	NM_000367.5	c.626-453G>T		intron_variant		ENST00000309983.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPMT	ENST00000309983.5	c.626-453G>T		intron_variant		1	NM_000367.5	P1

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92443 AN: 151936 Hom.: 29851 Cov.: 33

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.624

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.608 AC: 92451 AN: 152054 Hom.: 29845 Cov.: 33 AF XY: 0.606 AC XY: 45059 AN XY: 74308

Gnomad4 AFR AF: 0.367

Gnomad4 AMR AF: 0.628

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.743

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.688

Gnomad4 NFE AF: 0.720

Gnomad4 OTH AF: 0.623

Alfa AF: 0.697 Hom.: 58241

Bravo AF: 0.597

Asia WGS AF: 0.645 AC: 2240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.3
Dann	Benign	0.71

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: rs9367980; hg19: chr6-18131464;