NM_000367.5:c.233+35C>T

Variant names:

• chr6-18147788-G-A
• rs4449636
• NM_000367.5:c.233+35C>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+35C>T 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 1,570,128 control chromosomes in the GnomAD database, including 228,187 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 (25351 hom., cov: 33)
  • Exomes 𝑓: 0.53 (202836 hom.)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.233+35C>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+35C>T		intron_variant	Intron 3 of 8	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1	n.268-1700G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86740 AN: 151910 Hom.: 25310 Cov.: 33

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.535

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.519 AC: 129684 AN: 249814 AF XY: 0.512

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.477

Gnomad EAS exome AF: 0.350

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.533 AC: 756083 AN: 1418100 Hom.: 202836 Cov.: 23 AF XY: 0.528 AC XY: 373929 AN XY: 707994

African (AFR) AF: 0.698 AC: 22777 AN: 32642

American (AMR) AF: 0.572 AC: 25435 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 12386 AN: 25816

East Asian (EAS) AF: 0.385 AC: 15163 AN: 39392

South Asian (SAS) AF: 0.439 AC: 37243 AN: 84820

European-Finnish (FIN) AF: 0.536 AC: 28596 AN: 53360

Middle Eastern (MID) AF: 0.503 AC: 2385 AN: 4740

European-Non Finnish (NFE) AF: 0.541 AC: 581205 AN: 1073966

Other (OTH) AF: 0.525 AC: 30893 AN: 58878

GnomAD4 genome AF: 0.571 AC: 86839 AN: 152028 Hom.: 25351 Cov.: 33 AF XY: 0.568 AC XY: 42214 AN XY: 74286

African (AFR) AF: 0.692 AC: 28703 AN: 41468

American (AMR) AF: 0.563 AC: 8587 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1642 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1931 AN: 5172

South Asian (SAS) AF: 0.437 AC: 2106 AN: 4824

European-Finnish (FIN) AF: 0.529 AC: 5577 AN: 10542

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.535 AC: 36382 AN: 67978

Other (OTH) AF: 0.553 AC: 1166 AN: 2108

Alfa AF: 0.546 Hom.: 60919

Bravo AF: 0.581

Asia WGS AF: 0.448 AC: 1559 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.61
PhyloP100		0.0050
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: rs4449636; hg19: chr6-18148019; COSMIC: COSV59429008;