6-18138997-C-T

Variant names:

• chr6-18138997-C-T
• rs1800460
• NM_000367.5:c.460G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: -0.0930
• Publications: 333 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008158416).
• BP6: Variant 6-18138997-C-T is Benign according to our data. Variant chr6-18138997-C-T is described in ClinVar as [Likely_benign, other]. Clinvar id is 37126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.460G>A	p.Ala154Thr	missense_variant	Exon 6 of 9	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.460G>A	p.Ala154Thr	missense_variant	Exon 6 of 9	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1	n.268-10491C>T		intron_variant	Intron 1 of 2

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

GnomAD2 exomes AF: 0.0280 AC: 7048 AN: 251358 AF XY: 0.0266

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 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

African (AFR) AF: 0.00583 AC: 195 AN: 33474

American (AMR) AF: 0.0430 AC: 1920 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 398 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00651 AC: 561 AN: 86232

European-Finnish (FIN) AF: 0.0271 AC: 1446 AN: 53416

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.0418 AC: 46369 AN: 1109656

Other (OTH) AF: 0.0280 AC: 1688 AN: 60330

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

African (AFR) AF: 0.00722 AC: 300 AN: 41578

American (AMR) AF: 0.0385 AC: 589 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4834

European-Finnish (FIN) AF: 0.0265 AC: 281 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0382 AC: 2598 AN: 68022

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0326 Hom.: 124

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: Benign/Likely benign; other

Submissions summary: Benign:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Mar 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 11, 2015

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPMT: BS1, BS2 -

TPMT-related disorder Benign:1

Jul 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 01, 1999

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		-0.093
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
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs1800460; hg19: chr6-18139228; COSMIC: COSV59428264;