rs4449636

Positions:

• chr6-18147788-G-A
• chr6-18147788-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-18147788-G-A is Benign according to our data. Variant chr6-18147788-G-A is described in Lovd as [Benign]. Variant chr6-18147788-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
TPMT	NM_000367.5	c.233+35C>T		intron_variant		ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.233+35C>T		intron_variant		1	NM_000367.5	ENSP00000312304	P1

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

GnomAD3 exomes AF: 0.519 AC: 129684 AN: 249814 Hom.: 34438 AF XY: 0.512 AC XY: 69115 AN XY: 135104

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 SAS exome AF: 0.440

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

Gnomad4 AFR exome AF: 0.698

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.480

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.525

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

Gnomad4 AFR AF: 0.692

Gnomad4 AMR AF: 0.563

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.535

Gnomad4 OTH AF: 0.553

Alfa AF: 0.535 Hom.: 22603

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

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: rs4449636; hg19: chr6-18148019; COSMIC: COSV59429008;