rs2842951

Variant names:

• chr6-18135452-T-C
• rs2842951
• NM_000367.5:c.495-1563A>G

Variant summary

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

The NM_000367.5(TPMT):​c.495-1563A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 152,038 control chromosomes in the GnomAD database, including 34,569 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 0.66 (34569 hom., cov: 32)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443
• Publications: 6 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.495-1563A>G		intron_variant	Intron 6 of 8	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.495-1563A>G		intron_variant	Intron 6 of 8	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1	n.267+12346T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99936 AN: 151920 Hom.: 34579 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.671

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.657 AC: 99951 AN: 152038 Hom.: 34569 Cov.: 32 AF XY: 0.656 AC XY: 48752 AN XY: 74320

African (AFR) AF: 0.424 AC: 17566 AN: 41438

American (AMR) AF: 0.699 AC: 10682 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2461 AN: 3472

East Asian (EAS) AF: 0.814 AC: 4214 AN: 5178

South Asian (SAS) AF: 0.653 AC: 3146 AN: 4818

European-Finnish (FIN) AF: 0.721 AC: 7626 AN: 10572

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51906 AN: 67968

Other (OTH) AF: 0.669 AC: 1412 AN: 2110

Alfa AF: 0.733 Hom.: 67111

Bravo AF: 0.650

Asia WGS AF: 0.696 AC: 2417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.58
DANN	Benign	0.45
PhyloP100		-0.44
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: rs2842951; hg19: chr6-18135683;