8-33503800-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001102401.4(TTI2):c.1063C>T(p.Arg355Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00459 in 1,614,010 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 17 hom. )

Consequence

TTI2
NM_001102401.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.54

Publications

8 publications found

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]

TTI2 Gene-Disease associations (from GenCC):

severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

TTI2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011873692).

BP6

Variant 8-33503800-G-A is Benign according to our data. Variant chr8-33503800-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437081.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00371 (565/152230) while in subpopulation NFE AF = 0.00534 (363/68018). AF 95% confidence interval is 0.00488. There are 2 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTI2	NM_001102401.4 link	c.1063C>T	p.Arg355Cys	missense_variant	Exon 5 of 8	ENST00000431156.7	NP_001095871.1	Q6NXR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTI2	ENST00000431156.7 link	c.1063C>T	p.Arg355Cys	missense_variant	Exon 5 of 8	1	NM_001102401.4	ENSP00000411169.3		Q6NXR4

Frequencies

GnomAD3 genomes

AF:

0.00371

AC:

565

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0114

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00534

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00308

AC:

773

AN:

251170

AF XY:

0.00296

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad FIN exome

AF:

0.00763

Gnomad NFE exome

AF:

0.00468

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00468

AC:

6846

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00455

AC XY:

3311

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33478

American (AMR)

AF:

0.000738

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.000858

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00743

AC:

397

AN:

53418

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00547

AC:

6077

AN:

1111984

Other (OTH)

AF:

0.00391

AC:

236

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

392

784

1177

1569

1961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00371

AC:

565

AN:

152230

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41524

American (AMR)

AF:

0.000720

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0114

AC:

121

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00534

AC:

363

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00416

Hom.:

Bravo

AF:

0.00272

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00308

AC:

374

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTI2: BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 16, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;.;.;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.068

MutationAssessor

Uncertain

2.6

M;M;M;.

PhyloP100

4.5

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.7

.;D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.67

MVP

0.83

MPC

0.73

ClinPred

0.055

GERP RS

5.5

Varity_R

0.44

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over