rs75543815

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000367.5(TPMT):​c.539A>T​(p.Tyr180Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,611,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

TPMT
NM_000367.5 missense

Scores

1
2
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.36
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0761224).
BP6
Variant 6-18133845-T-A is Benign according to our data. Variant chr6-18133845-T-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPMTNM_000367.5 linkuse as main transcriptc.539A>T p.Tyr180Phe missense_variant 7/9 ENST00000309983.5 NP_000358.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPMTENST00000309983.5 linkuse as main transcriptc.539A>T p.Tyr180Phe missense_variant 7/91 NM_000367.5 ENSP00000312304 P1

Frequencies

GnomAD3 genomes
AF:
0.0000932
AC:
14
AN:
150180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00272
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000195
AC:
49
AN:
251380
Hom.:
0
AF XY:
0.000191
AC XY:
26
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00256
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000951
AC:
139
AN:
1461630
Hom.:
0
Cov.:
33
AF XY:
0.0000908
AC XY:
66
AN XY:
727138
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00330
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000932
AC:
14
AN:
150208
Hom.:
0
Cov.:
33
AF XY:
0.000137
AC XY:
10
AN XY:
73142
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00273
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000679
Hom.:
0
Bravo
AF:
0.000147
ExAC
AF:
0.000189
AC:
23
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.20
T
Eigen
Benign
0.084
Eigen_PC
Benign
0.035
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.076
T
MetaSVM
Benign
-0.65
T
MutationAssessor
Pathogenic
3.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.29
Sift
Benign
0.12
T
Sift4G
Benign
0.48
T
Polyphen
0.94
P
Vest4
0.43
MVP
0.67
MPC
0.25
ClinPred
0.23
T
GERP RS
5.3
Varity_R
0.67
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs75543815; hg19: chr6-18134076; API