NM_000367.5:c.580+14G>T

Variant names:

• chr6-18133790-C-A
• rs2842949
• NM_000367.5:c.580+14G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000367.5(TPMT):​c.580+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 1,548,776 control chromosomes in the GnomAD database, including 378,858 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29317 hom., cov: 30)
  • Exomes 𝑓: 0.70 (349541 hom.)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680
• Publications: 8 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 (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.580+14G>T		intron_variant	Intron 7 of 8	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.580+14G>T		intron_variant	Intron 7 of 8	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1	n.267+10684C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.620 AC: 90982 AN: 146846 Hom.: 29327 Cov.: 30

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.641

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.630

GnomAD2 exomes AF: 0.669 AC: 143254 AN: 214212 AF XY: 0.672

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.685

Gnomad EAS exome AF: 0.757

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.710

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.704 AC: 987431 AN: 1401876 Hom.: 349541 Cov.: 29 AF XY: 0.703 AC XY: 490966 AN XY: 698166

African (AFR) AF: 0.362 AC: 10665 AN: 29486

American (AMR) AF: 0.664 AC: 23875 AN: 35978

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 17160 AN: 24760

East Asian (EAS) AF: 0.737 AC: 28833 AN: 39128

South Asian (SAS) AF: 0.620 AC: 48719 AN: 78574

European-Finnish (FIN) AF: 0.697 AC: 36084 AN: 51744

Middle Eastern (MID) AF: 0.673 AC: 3708 AN: 5512

European-Non Finnish (NFE) AF: 0.722 AC: 778810 AN: 1078834

Other (OTH) AF: 0.684 AC: 39577 AN: 57860

GnomAD4 genome AF: 0.619 AC: 90972 AN: 146900 Hom.: 29317 Cov.: 30 AF XY: 0.617 AC XY: 44118 AN XY: 71478

African (AFR) AF: 0.393 AC: 15175 AN: 38624

American (AMR) AF: 0.631 AC: 9472 AN: 15006

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2382 AN: 3456

East Asian (EAS) AF: 0.759 AC: 3864 AN: 5094

South Asian (SAS) AF: 0.608 AC: 2900 AN: 4768

European-Finnish (FIN) AF: 0.685 AC: 6454 AN: 9418

Middle Eastern (MID) AF: 0.643 AC: 175 AN: 272

European-Non Finnish (NFE) AF: 0.721 AC: 48519 AN: 67286

Other (OTH) AF: 0.630 AC: 1302 AN: 2068

Alfa AF: 0.725 Hom.: 10272

Bravo AF: 0.599

Asia WGS AF: 0.637 AC: 2143 AN: 3368

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.26
PhyloP100		0.068
Mutation Taster		=100/0	polymorphism (auto)

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: rs2842949; hg19: chr6-18134021; COSMIC: COSV59428486;