rs369757546
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001102401.4(TTI2):c.695C>T(p.Thr232Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,600,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000060 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000039 ( 0 hom. )
Consequence
TTI2
NM_001102401.4 missense
NM_001102401.4 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 1.55
Genes affected
TTI2 (HGNC:26262): (TELO2 interacting protein 2) This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTI2 | NM_001102401.4 | c.695C>T | p.Thr232Ile | missense_variant | 3/8 | ENST00000431156.7 | NP_001095871.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTI2 | ENST00000431156.7 | c.695C>T | p.Thr232Ile | missense_variant | 3/8 | 1 | NM_001102401.4 | ENSP00000411169 | P1 | |
TTI2 | ENST00000613904.1 | c.695C>T | p.Thr232Ile | missense_variant | 3/8 | 1 | ENSP00000478396 | P1 | ||
TTI2 | ENST00000360742.9 | c.695C>T | p.Thr232Ile | missense_variant | 2/7 | 2 | ENSP00000353971 | P1 | ||
TTI2 | ENST00000520636.5 | c.695C>T | p.Thr232Ile | missense_variant | 2/6 | 5 | ENSP00000428401 |
Frequencies
GnomAD3 genomes AF: 0.0000600 AC: 9AN: 150052Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251460Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
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GnomAD4 exome AF: 0.0000386 AC: 56AN: 1450910Hom.: 0 Cov.: 33 AF XY: 0.0000346 AC XY: 25AN XY: 721842
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GnomAD4 genome AF: 0.0000600 AC: 9AN: 150052Hom.: 0 Cov.: 30 AF XY: 0.0000548 AC XY: 4AN XY: 73008
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 12, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2023 | The c.695C>T (p.T232I) alteration is located in exon 2 (coding exon 2) of the TTI2 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the threonine (T) at amino acid position 232 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 24, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;.;.;T
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;N
REVEL
Benign
Sift
Benign
.;T;T;T
Sift4G
Uncertain
D;D;D;D
Polyphen
P;P;P;P
Vest4
MVP
MPC
0.24
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at