6-18138997-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000367.5(TPMT):c.460G>A(p.Ala154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,611,706 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (73 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1188 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Likely benign; other criteria provided, multiple submitters, no conflicts B:2 O:2
• Conservation: PhyloP100: -0.0930

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 (MetaRNN=0.008158416).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0258 (3933/152312) while in subpopulation AMR AF= 0.0385 (589/15298). AF 95% confidence interval is 0.037. There are 73 homozygotes in gnomad4. There are 1887 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 74 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPMT	NM_000367.5	c.460G>A	p.Ala154Thr	missense_variant	6/9	ENST00000309983.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPMT	ENST00000309983.5	c.460G>A	p.Ala154Thr	missense_variant	6/9	1	NM_000367.5	P1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3936 AN: 152194 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0386

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00599

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0280 AC: 7048 AN: 251358 Hom.: 160 AF XY: 0.0266 AC XY: 3619 AN XY: 135858

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00683

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0361 AC: 52612 AN: 1459394 Hom.: 1188 Cov.: 34 AF XY: 0.0349 AC XY: 25355 AN XY: 726138

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00651

Gnomad4 FIN exome AF: 0.0271

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0258 AC: 3933 AN: 152312 Hom.: 73 Cov.: 32 AF XY: 0.0253 AC XY: 1887 AN XY: 74482

Gnomad4 AFR AF: 0.00722

Gnomad4 AMR AF: 0.0385

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.0265

Gnomad4 NFE AF: 0.0382

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0335 Hom.: 104

Bravo AF: 0.0266

TwinsUK AF: 0.0461 AC: 171

ALSPAC AF: 0.0400 AC: 154

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0376 AC: 323

ExAC AF: 0.0275 AC: 3338

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0363

EpiControl AF: 0.0357

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2015	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

TPMT-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Thiopurine S-methyltransferase deficiency Other:1

drug response, no assertion criteria provided

literature only

OMIM

Feb 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.14
MPC		0.49
ClinPred		0.097	T
GERP RS		-0.48
Varity_R		0.92
gMVP		0.72

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: rs1800460; hg19: chr6-18139228; COSMIC: COSV59428264;