rs6921269

Variant names:

• chr6-18133847-C-A
• rs6921269
• NM_000367.5:c.537G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-18133847-C-A
• chr6-18133847-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000367.5(TPMT):​c.537G>T​(p.Gln179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,611,974 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0065 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (10 hom.)
• Consequence: TPMT NM_000367.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 23 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01912865).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00646 (972/150470) while in subpopulation AFR AF = 0.022 (907/41134). AF 95% confidence interval is 0.0209. There are 15 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	NM_000367.5	MANE Select	c.537G>T	p.Gln179His	missense	Exon 7 of 9	NP_000358.1
	TPMT	NM_001346817.1		c.537G>T	p.Gln179His	missense	Exon 8 of 10	NP_001333746.1
	TPMT	NM_001346818.1		c.537G>T	p.Gln179His	missense	Exon 7 of 8	NP_001333747.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPMT	ENST00000309983.5	TSL:1 MANE Select	c.537G>T	p.Gln179His	missense	Exon 7 of 9	ENSP00000312304.4
	ENSG00000307971	ENST00000830125.1		n.267+10741C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 969 AN: 150438 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00629

GnomAD2 exomes AF: 0.00164 AC: 413 AN: 251380 AF XY: 0.00121

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000636 AC: 929 AN: 1461504 Hom.: 10 Cov.: 33 AF XY: 0.000532 AC XY: 387 AN XY: 727064

African (AFR) AF: 0.0229 AC: 767 AN: 33464

American (AMR) AF: 0.00136 AC: 61 AN: 44710

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111778

Other (OTH) AF: 0.00142 AC: 86 AN: 60366

GnomAD4 genome AF: 0.00646 AC: 972 AN: 150470 Hom.: 15 Cov.: 33 AF XY: 0.00632 AC XY: 463 AN XY: 73310

African (AFR) AF: 0.0220 AC: 907 AN: 41134

American (AMR) AF: 0.00311 AC: 47 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9754

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

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67828

Other (OTH) AF: 0.00624 AC: 13 AN: 2082

Alfa AF: 0.00220 Hom.: 3

Bravo AF: 0.00745

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0020
DANN	Benign	0.58
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		-2.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.029
Sift	Benign	0.20	T
Sift4G	Benign	0.14	T
Polyphen		0.0070	B
Vest4		0.036
MutPred		0.27		Loss of catalytic residue at Q179 (P = 0.0927)
MVP		0.41
MPC		0.13
ClinPred		0.0060	T
GERP RS		-4.9
Varity_R		0.058
gMVP		0.57
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6921269; hg19: chr6-18134078;