6-18147549-G-A

Variant names:

• chr6-18147549-G-A
• rs3898137
• NM_000367.5:c.233+274C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000367.5(TPMT):​c.233+274C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 152,022 control chromosomes in the GnomAD database, including 8,817 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 0.33 (8817 hom., cov: 33)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.499
• Publications: 10 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.233+274C>T		intron_variant	Intron 3 of 8	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.233+274C>T		intron_variant	Intron 3 of 8	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1	n.268-1939G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49691 AN: 151902 Hom.: 8817 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.327 AC: 49688 AN: 152022 Hom.: 8817 Cov.: 33 AF XY: 0.328 AC XY: 24341 AN XY: 74302

African (AFR) AF: 0.200 AC: 8277 AN: 41462

American (AMR) AF: 0.327 AC: 4990 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1266 AN: 3466

East Asian (EAS) AF: 0.254 AC: 1313 AN: 5172

South Asian (SAS) AF: 0.248 AC: 1197 AN: 4822

European-Finnish (FIN) AF: 0.444 AC: 4690 AN: 10552

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26675 AN: 67946

Other (OTH) AF: 0.328 AC: 693 AN: 2114

Alfa AF: 0.365 Hom.: 17447

Bravo AF: 0.316

Asia WGS AF: 0.257 AC: 897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.64
PhyloP100		0.50
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: rs3898137; hg19: chr6-18147780;