chr6-18139041-C-T

Variant names:

• chr6-18139041-C-T
• rs56019966
• NM_000367.5:c.420-4G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000367.5(TPMT):​c.420-4G>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0001031
• Clinical Significance: Likely benign; drug response no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 0.324
• Publications: 5 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 -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 rank	MANE	Protein	UniProt
TPMT	NM_000367.5	c.420-4G>A		splice_region_variant, intron_variant	Intron 5 of 8	ENST00000309983.5	NP_000358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPMT	ENST00000309983.5	c.420-4G>A		splice_region_variant, intron_variant	Intron 5 of 8	1	NM_000367.5	ENSP00000312304.4
ENSG00000307971	ENST00000830125.1	n.268-10447C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152136 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00129 AC: 325 AN: 251384 AF XY: 0.00124

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 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.: 10 Cov.: 33 AF XY: 0.00217 AC XY: 1574 AN XY: 726782

African (AFR) AF: 0.000329 AC: 11 AN: 33456

American (AMR) AF: 0.000671 AC: 30 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86238

European-Finnish (FIN) AF: 0.00120 AC: 64 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00266 AC: 2950 AN: 1111016

Other (OTH) AF: 0.00186 AC: 112 AN: 60364

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74424

African (AFR) AF: 0.000385 AC: 16 AN: 41552

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00250 AC: 170 AN: 68024

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00127

EpiCase AF: 0.00251

EpiControl AF: 0.00314

ClinVar

Significance: Likely benign; drug response

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

TPMT-related disorder Benign:1

Oct 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 21, 2010

Neurology IV Unit; Fondazione Istituto Neurologico C. Besta

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

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
PhyloP100		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs56019966; hg19: chr6-18139272;