chr8-33503741-G-C

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.1115+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,613,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

TTI2
NM_001102401.4 splice_region, intron

Scores

Splicing: ADA: 0.00002236

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -2.19

Publications

0 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 (BayesDel_noAF=-0.91).

BP6

Variant 8-33503741-G-C is Benign according to our data. Variant chr8-33503741-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437087.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00169 (257/152252) while in subpopulation AFR AF = 0.00568 (236/41546). AF 95% confidence interval is 0.00509. There are 2 homozygotes in GnomAd4. There are 123 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.1115+7C>G		splice_region_variant, intron_variant	Intron 5 of 7	ENST00000431156.7	NP_001095871.1	Q6NXR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTI2	ENST00000431156.7 link	c.1115+7C>G		splice_region_variant, intron_variant	Intron 5 of 7	1	NM_001102401.4	ENSP00000411169.3		Q6NXR4

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00570

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000325

AC:

AN:

249058

AF XY:

0.000245

show subpopulations

Gnomad AFR exome

AF:

0.00409

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

233

AN:

1460896

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.00541

AC:

181

AN:

33448

American (AMR)

AF:

0.000336

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000942

AC:

AN:

5308

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111756

Other (OTH)

AF:

0.000332

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00169

AC:

257

AN:

152252

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00568

AC:

236

AN:

41546

American (AMR)

AF:

0.000916

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.000203

Hom.:

Bravo

AF:

0.00187

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TTI2: BP4, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 03, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TTI2-related disorder

Benign:1

Mar 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.20

(source)

DANN

Benign

0.66

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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