Variant 6-18139041-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000367.5(TPMT):c.420-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,054 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign,drug response (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 10 hom. )

Consequence

TPMT
NM_000367.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001031

Clinical Significance

Likely benign; drug response no assertion criteria provided B:1O:1

Conservation

PhyloP100: 0.324

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 6-18139041-C-T is Benign according to our data. Variant chr6-18139041-C-T is described in ClinVar as [Likely_benign, drug_response]. Clinvar id is 143913.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPMT	NM_000367.5 linkuse as main transcript	c.420-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000309983.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPMT	ENST00000309983.5 linkuse as main transcript	c.420-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000367.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.00129

AC:

325

AN:

251384

Hom.:

AF XY:

0.00124

AC XY:

169

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00219

AC:

3195

AN:

1460800

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1574

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00120

Gnomad4 NFE exome

AF:

0.00266

Gnomad4 OTH exome

AF:

0.00186

GnomAD4 genome

AF:

0.00135

AC:

206

AN:

152254

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00250

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.00168

Hom.:

Bravo

AF:

0.00127

EpiCase

AF:

0.00251

EpiControl

AF:

0.00314

ClinVar

Significance: Likely benign; drug response

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TPMT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Azathioprine response

Other:1

drug response, no assertion criteria provided

research

Neurology IV Unit; Fondazione Istituto Neurologico C. Besta

Dec 21, 2010

The variant is clinically significant because of its association with azathioprine intolerance and a moderate TPMT activity, evidenced by reduced activity of TPMT tested on red blood cells by ELISA. azathioprine intolerance

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.7

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.0080

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