chr6-18133845-T-A

Variant names:

• chr6-18133845-T-A
• rs75543815
• NM_000367.5:c.539A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000367.5(TPMT):​c.539A>T​(p.Tyr180Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,611,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 21 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0761224).

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.539A>T	p.Tyr180Phe	missense	Exon 7 of 9	NP_000358.1	P51580
	TPMT	NM_001346817.1		c.539A>T	p.Tyr180Phe	missense	Exon 8 of 10	NP_001333746.1	P51580
	TPMT	NM_001346818.1		c.539A>T	p.Tyr180Phe	missense	Exon 7 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.539A>T	p.Tyr180Phe	missense	Exon 7 of 9	ENSP00000312304.4	P51580
	TPMT	ENST00000864360.1		c.539A>T	p.Tyr180Phe	missense	Exon 8 of 10	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.539A>T	p.Tyr180Phe	missense	Exon 7 of 9	ENSP00000534421.1

Frequencies

GnomAD3 genomes AF: 0.0000932 AC: 14 AN: 150180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251380 AF XY: 0.000191

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461630 Hom.: 0 Cov.: 33 AF XY: 0.0000908 AC XY: 66 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00330 AC: 131 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111864

Other (OTH) AF: 0.0000994 AC: 6 AN: 60374

GnomAD4 genome AF: 0.0000932 AC: 14 AN: 150208 Hom.: 0 Cov.: 33 AF XY: 0.000137 AC XY: 10 AN XY: 73142

African (AFR) AF: 0.00 AC: 0 AN: 41064

American (AMR) AF: 0.00 AC: 0 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00273 AC: 14 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67800

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000679 Hom.: 0

Bravo AF: 0.000147

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.084
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.29
Sift	Benign	0.12	T
Sift4G	Benign	0.48	T
Polyphen		0.94	P
Vest4		0.43
MVP		0.67
MPC		0.25
ClinPred		0.23	T
GERP RS		5.3
Varity_R		0.67
gMVP		0.67
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75543815; hg19: chr6-18134076;