6-18130702-A-T

Variant names:

• chr6-18130702-A-T
• rs781105138
• NM_000367.5:c.704T>A

Variant summary

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

The NM_000367.5(TPMT):​c.704T>A​(p.Leu235His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,454 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L235P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75
• Publications: 0 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.704T>A	p.Leu235His	missense	Exon 9 of 9	NP_000358.1	P51580
	TPMT	NM_001346817.1		c.704T>A	p.Leu235His	missense	Exon 10 of 10	NP_001333746.1	P51580
	TPMT	NM_001346818.1		c.659T>A	p.Leu220His	missense	Exon 8 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.704T>A	p.Leu235His	missense	Exon 9 of 9	ENSP00000312304.4	P51580
	TPMT	ENST00000864360.1		c.704T>A	p.Leu235His	missense	Exon 10 of 10	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.704T>A	p.Leu235His	missense	Exon 9 of 9	ENSP00000534421.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460454 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726566

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4900

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111738

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.8
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.014	D
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.19
MutPred		0.80		Loss of stability (P = 0.0104)
MVP		0.80
MPC		0.68
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.62
gMVP		0.84
Mutation Taster		=93/7	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: rs781105138; hg19: chr6-18130933;