16-52439588-C-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001080430.4(TOX3):c.1368G>C(p.Met456Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000503 in 1,591,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )
Consequence
TOX3
NM_001080430.4 missense
NM_001080430.4 missense
Scores
1
2
14
Clinical Significance
Conservation
PhyloP100: 5.75
Genes affected
TOX3 (HGNC:11972): (TOX high mobility group box family member 3) The protein encoded by this gene contains an HMG-box, indicating that it may be involved in bending and unwinding of DNA and alteration of chromatin structure. The C-terminus of the encoded protein is glutamine-rich due to CAG repeats in the coding sequence. A minor allele of this gene has been implicated in an elevated risk of breast cancer. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15114453).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TOX3 | NM_001080430.4 | c.1368G>C | p.Met456Ile | missense_variant | 7/7 | ENST00000219746.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TOX3 | ENST00000219746.14 | c.1368G>C | p.Met456Ile | missense_variant | 7/7 | 2 | NM_001080430.4 | A2 | |
TOX3 | ENST00000407228.7 | c.1353G>C | p.Met451Ile | missense_variant | 8/8 | 2 | P2 | ||
TOX3 | ENST00000566696.1 | n.1832G>C | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151960Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000133 AC: 3AN: 225884Hom.: 0 AF XY: 0.0000164 AC XY: 2AN XY: 121858
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GnomAD4 exome AF: 0.00000417 AC: 6AN: 1439578Hom.: 0 Cov.: 28 AF XY: 0.00000419 AC XY: 3AN XY: 715334
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74222
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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 submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | The c.1368G>C (p.M456I) alteration is located in exon 7 (coding exon 7) of the TOX3 gene. This alteration results from a G to C substitution at nucleotide position 1368, causing the methionine (M) at amino acid position 456 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Pathogenic
D;D
Sift4G
Benign
T;T
Polyphen
0.0
.;B
Vest4
MutPred
0.49
.;Gain of MoRF binding (P = 0.1776);
MVP
MPC
0.24
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at