NM_000367.5:c.690G>C

Variant names:

• chr6-18130716-C-G
• NM_000367.5:c.690G>C

Variant summary

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

The NM_000367.5(TPMT):​c.690G>C​(p.Trp230Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12
• 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.690G>C	p.Trp230Cys	missense	Exon 9 of 9	NP_000358.1	P51580
	TPMT	NM_001346817.1		c.690G>C	p.Trp230Cys	missense	Exon 10 of 10	NP_001333746.1	P51580
	TPMT	NM_001346818.1		c.645G>C	p.Trp215Cys	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.690G>C	p.Trp230Cys	missense	Exon 9 of 9	ENSP00000312304.4	P51580
	TPMT	ENST00000864360.1		c.690G>C	p.Trp230Cys	missense	Exon 10 of 10	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.690G>C	p.Trp230Cys	missense	Exon 9 of 9	ENSP00000534421.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461010 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726836

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.60		Gain of methylation at K228 (P = 0.0778)
MVP		0.87
MPC		0.73
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.87
Mutation Taster		=16/84	disease causing

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

hg19: chr6-18130947;