chr13-45339541-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003295.4(TPT1):​c.355G>T​(p.Ala119Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,816 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 ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

TPT1
NM_003295.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09
Variant links:
Genes affected
TPT1 (HGNC:12022): (tumor protein, translationally-controlled 1) This gene encodes a protein that is a regulator of cellular growth and proliferation. Its mRNA is highly structured and contains an oligopyrimidine tract (5'-TOP) in its 5' untranslated region that functions to repress its translation under quiescent conditions. The encoded protein is involved in a variety of cellular pathways, including apoptosis, protein synthesis and cell division. It binds to and stabilizes microtubules, and removal of this protein through phosphorylation is required for progression through mitotic and meiotic cell divisions. This gene is known to play a role in carcinogenesis, and is upregulated in some cancer cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10408789).
BS2
High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPT1NM_003295.4 linkc.355G>T p.Ala119Ser missense_variant 4/6 ENST00000530705.6 NP_003286.1 P13693-1A0A0P1J1R0
TPT1NM_001286272.2 linkc.355G>T p.Ala119Ser missense_variant 4/6 NP_001273201.1 A0A0B4J2C3
TPT1NM_001286273.2 linkc.253G>T p.Ala85Ser missense_variant 3/5 NP_001273202.1 P13693-2A0A024RDY2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPT1ENST00000530705.6 linkc.355G>T p.Ala119Ser missense_variant 4/61 NM_003295.4 ENSP00000431872.2 P13693-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251206
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000695
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461594
Hom.:
0
Cov.:
30
AF XY:
0.0000179
AC XY:
13
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000727
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000158
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 13, 2023The c.355G>T (p.A119S) alteration is located in exon 4 (coding exon 4) of the TPT1 gene. This alteration results from a G to T substitution at nucleotide position 355, causing the alanine (A) at amino acid position 119 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
25
DANN
Benign
0.97
DEOGEN2
Benign
0.22
.;T;.;T;.;T;.
Eigen
Benign
-0.099
Eigen_PC
Benign
0.043
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.66
T;T;.;T;T;T;T
M_CAP
Benign
0.0089
T
MetaRNN
Benign
0.10
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
.;L;.;.;.;.;.
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.4
.;N;N;N;N;N;N
REVEL
Benign
0.055
Sift
Benign
0.38
.;T;T;T;T;T;T
Sift4G
Benign
0.48
T;T;T;T;T;T;T
Polyphen
0.0010
.;B;.;.;.;.;.
Vest4
0.45
MutPred
0.44
Gain of catalytic residue at I122 (P = 8e-04);Gain of catalytic residue at I122 (P = 8e-04);.;.;.;Gain of catalytic residue at I122 (P = 8e-04);.;
MVP
0.17
MPC
0.49
ClinPred
0.10
T
GERP RS
3.9
Varity_R
0.27
gMVP
0.19

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: rs779614359; hg19: chr13-45913676; API