6-18143627-A-T

Variant names:

• chr6-18143627-A-T
• rs886061266
• NM_000367.5:c.335T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000367.5(TPMT):​c.335T>A​(p.Ile112Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000367.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	NM_000367.5	MANE Select	c.335T>A	p.Ile112Asn	missense	Exon 4 of 9	NP_000358.1	P51580
	TPMT	NM_001346817.1		c.335T>A	p.Ile112Asn	missense	Exon 5 of 10	NP_001333746.1	P51580
	TPMT	NM_001346818.1		c.335T>A	p.Ile112Asn	missense	Exon 4 of 8	NP_001333747.1	P51580

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	ENST00000309983.5	TSL:1 MANE Select	c.335T>A	p.Ile112Asn	missense	Exon 4 of 9	ENSP00000312304.4	P51580
	TPMT	ENST00000864360.1		c.335T>A	p.Ile112Asn	missense	Exon 5 of 10	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.335T>A	p.Ile112Asn	missense	Exon 4 of 9	ENSP00000534421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Thiopurine S-methyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.5
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.57		Gain of relative solvent accessibility (P = 0.005)
MVP		0.86
MPC		0.31
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.78
gMVP		0.64
Mutation Taster		=79/21	polymorphism

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: rs886061266; hg19: chr6-18143858;