6-18138983-G-A

Variant names:

• chr6-18138983-G-A
• rs2842934
• NM_000367.5:c.474C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000367.5(TPMT):​c.474C>T​(p.Ile158Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 1,611,978 control chromosomes in the GnomAD database, including 487,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (45952 hom., cov: 32)
  • Exomes 𝑓: 0.78 (441621 hom.)
• Consequence: TPMT NM_000367.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.171

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 6-18138983-G-A is Benign according to our data. Variant chr6-18138983-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 356114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18138983-G-A is described in Lovd as [Benign]. Variant chr6-18138983-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.171 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.474C>T	p.Ile158Ile	synonymous_variant	Exon 6 of 9	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.474C>T	p.Ile158Ile	synonymous_variant	Exon 6 of 9	1	NM_000367.5	ENSP00000312304.4

Frequencies

GnomAD3 genomes AF: 0.776 AC: 118039 AN: 152030 Hom.: 45929 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.761 AC: 191319 AN: 251334 AF XY: 0.754

Gnomad AFR exome AF: 0.815

Gnomad AMR exome AF: 0.766

Gnomad ASJ exome AF: 0.720

Gnomad EAS exome AF: 0.779

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.786

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.777 AC: 1133634 AN: 1459830 Hom.: 441621 Cov.: 47 AF XY: 0.772 AC XY: 560897 AN XY: 726330

Gnomad4 AFR exome AF: 0.810 AC: 27088 AN: 33446

Gnomad4 AMR exome AF: 0.764 AC: 34155 AN: 44704

Gnomad4 ASJ exome AF: 0.721 AC: 18840 AN: 26116

Gnomad4 EAS exome AF: 0.740 AC: 29388 AN: 39696

Gnomad4 SAS exome AF: 0.644 AC: 55501 AN: 86182

Gnomad4 FIN exome AF: 0.762 AC: 40721 AN: 53414

Gnomad4 NFE exome AF: 0.791 AC: 877651 AN: 1110176

Gnomad4 Remaining exome AF: 0.765 AC: 46147 AN: 60336

GnomAD4 genome AF: 0.776 AC: 118116 AN: 152148 Hom.: 45952 Cov.: 32 AF XY: 0.770 AC XY: 57229 AN XY: 74362

Gnomad4 AFR AF: 0.812 AC: 0.812368 AN: 0.812368

Gnomad4 AMR AF: 0.742 AC: 0.741691 AN: 0.741691

Gnomad4 ASJ AF: 0.719 AC: 0.719182 AN: 0.719182

Gnomad4 EAS AF: 0.760 AC: 0.759653 AN: 0.759653

Gnomad4 SAS AF: 0.628 AC: 0.627642 AN: 0.627642

Gnomad4 FIN AF: 0.742 AC: 0.741575 AN: 0.741575

Gnomad4 NFE AF: 0.782 AC: 0.782321 AN: 0.782321

Gnomad4 OTH AF: 0.762 AC: 0.762062 AN: 0.762062

Alfa AF: 0.782 Hom.: 203676

Bravo AF: 0.783

Asia WGS AF: 0.698 AC: 2428 AN: 3478

EpiCase AF: 0.778

EpiControl AF: 0.773

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Quick notes: Silent, In 75% of chromosomes. Unlikely to have PGx role -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.3
DANN	Benign	0.68
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

Publications

LitVar

Other links and lift over

dbSNP: rs2842934; hg19: chr6-18139214; COSMIC: COSV59429867;