Genetic Variant NM_000367.5:c.474C>T (chr6-18138983-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.171

Variant links:

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]

TPMT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 link	c.474C>T	p.Ile158Ile	synonymous_variant	Exon 6 of 9	ENST00000309983.5	NP_000358.1	P51580A0A024QZW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5 link	c.474C>T	p.Ile158Ile	synonymous_variant	Exon 6 of 9	1	NM_000367.5	ENSP00000312304.4		P51580

Frequencies

GnomAD3 genomes

AF:

0.776

AC:

118039

AN:

152030

Hom.:

45929

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.761

AC:

191319

AN:

251334

Hom.:

73205

AF XY:

0.754

AC XY:

102428

AN XY:

135848

show subpopulations

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 SAS exome

AF:

0.646

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.:

AF XY:

0.772

AC XY:

560897

AN XY:

726330

show subpopulations

Gnomad4 AFR exome

AF:

0.810

Gnomad4 AMR exome

AF:

0.764

Gnomad4 ASJ exome

AF:

0.721

Gnomad4 EAS exome

AF:

0.740

Gnomad4 SAS exome

AF:

0.644

Gnomad4 FIN exome

AF:

0.762

Gnomad4 NFE exome

AF:

0.791

Gnomad4 OTH exome

AF:

0.765

GnomAD4 genome

AF:

0.776

AC:

118116

AN:

152148

Hom.:

45952

Cov.:

AF XY:

0.770

AC XY:

57229

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.812

Gnomad4 AMR

AF:

0.742

Gnomad4 ASJ

AF:

0.719

Gnomad4 EAS

AF:

0.760

Gnomad4 SAS

AF:

0.628

Gnomad4 FIN

AF:

0.742

Gnomad4 NFE

AF:

0.782

Gnomad4 OTH

AF:

0.762

Alfa

AF:

0.779

Hom.:

92822

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

LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over