rs1800462

Variant names:

• chr6-18143724-C-G
• rs1800462
• NM_000367.5:c.238G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000367.5(TPMT):​c.238G>C​(p.Ala80Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,984 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 2.18
• Publications: 247 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.124863535).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.238G>C	p.Ala80Pro	missense	Exon 4 of 9	NP_000358.1	P51580
	TPMT	NM_001346817.1		c.238G>C	p.Ala80Pro	missense	Exon 5 of 10	NP_001333746.1	P51580
	TPMT	NM_001346818.1		c.238G>C	p.Ala80Pro	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.238G>C	p.Ala80Pro	missense	Exon 4 of 9	ENSP00000312304.4	P51580
	TPMT	ENST00000864360.1		c.238G>C	p.Ala80Pro	missense	Exon 5 of 10	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.238G>C	p.Ala80Pro	missense	Exon 4 of 9	ENSP00000534421.1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 309 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00174 AC: 437 AN: 251094 AF XY: 0.00188

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00215 AC: 3142 AN: 1461730 Hom.: 9 Cov.: 32 AF XY: 0.00208 AC XY: 1510 AN XY: 727156

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.00376 AC: 168 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53358

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00249 AC: 2769 AN: 1111956

Other (OTH) AF: 0.00209 AC: 126 AN: 60388

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74438

African (AFR) AF: 0.000626 AC: 26 AN: 41552

American (AMR) AF: 0.00707 AC: 108 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00255

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.95
MPC		0.68
ClinPred		0.10	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.92
Mutation Taster		=41/59	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

dbSNP: rs1800462; hg19: chr6-18143955;