rs11964408

Variant names:

• chr6-18145676-C-T
• rs11964408
• NM_000367.5:c.234-1948G>A

Variant summary

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

The NM_000367.5(TPMT):​c.234-1948G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0576 in 152,250 control chromosomes in the GnomAD database, including 335 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 0.058 (335 hom., cov: 32)
• Consequence: TPMT NM_000367.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147
• Publications: 12 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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.234-1948G>A		intron	N/A	NP_000358.1	P51580
	TPMT	NM_001346817.1		c.234-1948G>A		intron	N/A	NP_001333746.1	P51580
	TPMT	NM_001346818.1		c.234-1948G>A		intron	N/A	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.234-1948G>A		intron	N/A	ENSP00000312304.4	P51580
	TPMT	ENST00000864360.1		c.234-1948G>A		intron	N/A	ENSP00000534419.1
	TPMT	ENST00000864362.1		c.234-1948G>A		intron	N/A	ENSP00000534421.1

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8752 AN: 152132 Hom.: 336 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0488

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

GnomAD4 genome AF: 0.0576 AC: 8767 AN: 152250 Hom.: 335 Cov.: 32 AF XY: 0.0559 AC XY: 4164 AN XY: 74442

African (AFR) AF: 0.105 AC: 4354 AN: 41542

American (AMR) AF: 0.0544 AC: 832 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5180

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4828

European-Finnish (FIN) AF: 0.0295 AC: 313 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0428 AC: 2909 AN: 68012

Other (OTH) AF: 0.0482 AC: 102 AN: 2114

Alfa AF: 0.0538 Hom.: 94

Bravo AF: 0.0623

Asia WGS AF: 0.0230 AC: 80 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.13
DANN	Benign	0.43
PhyloP100		-0.15
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: rs11964408; hg19: chr6-18145907;