rs369757546

chr8-33509885-G-Achr8-33509885-G-C

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. 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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]

ACMG classification

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	UniProt
TTI2	NM_001102401.4	c.695C>T	p.Thr232Ile	missense_variant	3/8	ENST00000431156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTI2	ENST00000431156.7	c.695C>T	p.Thr232Ile	missense_variant	3/8	1	NM_001102401.4	P1
TTI2	ENST00000613904.1	c.695C>T	p.Thr232Ile	missense_variant	3/8	1		P1
TTI2	ENST00000360742.9	c.695C>T	p.Thr232Ile	missense_variant	2/7	2		P1
TTI2	ENST00000520636.5	c.695C>T	p.Thr232Ile	missense_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.0000600 AC: 9 AN: 150052 Hom.: 0 Cov.: 30

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

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

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

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

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: 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
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

Other links and lift over

dbSNP: rs369757546; hg19: chr8-33367403;