rs369757546

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

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.55
Variant links:
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]

Genome browser will be placed here

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
TTI2NM_001102401.4 linkuse as main transcriptc.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
TTI2ENST00000431156.7 linkuse as main transcriptc.695C>T p.Thr232Ile missense_variant 3/81 NM_001102401.4 ENSP00000411169 P1
TTI2ENST00000613904.1 linkuse as main transcriptc.695C>T p.Thr232Ile missense_variant 3/81 ENSP00000478396 P1
TTI2ENST00000360742.9 linkuse as main transcriptc.695C>T p.Thr232Ile missense_variant 2/72 ENSP00000353971 P1
TTI2ENST00000520636.5 linkuse as main transcriptc.695C>T p.Thr232Ile missense_variant 2/65 ENSP00000428401

Frequencies

GnomAD3 genomes
AF:
0.0000600
AC:
9
AN:
150052
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000491
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000670
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000886
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251460
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
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:
0.0000386
AC:
56
AN:
1450910
Hom.:
0
Cov.:
33
AF XY:
0.0000346
AC XY:
25
AN XY:
721842
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000507
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000600
AC:
9
AN:
150052
Hom.:
0
Cov.:
30
AF XY:
0.0000548
AC XY:
4
AN XY:
73008
show subpopulations
Gnomad4 AFR
AF:
0.0000491
Gnomad4 AMR
AF:
0.0000670
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000886
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 12, 2016- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 14, 2023The 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 submitterclinical testingBaylor GeneticsDec 24, 2018This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0038
T;T;T;.
Eigen
Benign
0.088
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.72
T;.;.;T
M_CAP
Benign
0.025
D
MetaRNN
Uncertain
0.43
T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.5
L;L;L;.
MutationTaster
Benign
0.99
D;D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.52
.;N;N;N
REVEL
Benign
0.25
Sift
Benign
0.47
.;T;T;T
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
0.67
P;P;P;P
Vest4
0.53
MVP
0.42
MPC
0.24
ClinPred
0.20
T
GERP RS
3.1
Varity_R
0.025
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: -11

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: rs369757546; hg19: chr8-33367403; API