rs2842951

chr6-18135452-T-C

Variant summary

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

The NM_000367.5(TPMT):c.495-1563A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 152,038 control chromosomes in the GnomAD database, including 34,569 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 0.66 (34569 hom., cov: 32)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPMT	NM_000367.5	c.495-1563A>G		intron_variant		ENST00000309983.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPMT	ENST00000309983.5	c.495-1563A>G		intron_variant		1	NM_000367.5	P1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99936 AN: 151920 Hom.: 34579 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.671

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

GnomAD4 genome AF: 0.657 AC: 99951 AN: 152038 Hom.: 34569 Cov.: 32 AF XY: 0.656 AC XY: 48752 AN XY: 74320

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.709

Gnomad4 EAS AF: 0.814

Gnomad4 SAS AF: 0.653

Gnomad4 FIN AF: 0.721

Gnomad4 NFE AF: 0.764

Gnomad4 OTH AF: 0.669

Alfa AF: 0.744 Hom.: 53934

Bravo AF: 0.650

Asia WGS AF: 0.696 AC: 2417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.58
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: rs2842951; hg19: chr6-18135683;