rs78781527

Positions:

• chr8-33512496-G-A
• chr8-33512496-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000431156.7(TTI2):​c.118C>T​(p.Pro40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,082 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (60 hom.)
• Consequence: TTI2 ENST00000431156.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.628

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038638413).
• BP6: Variant 8-33512496-G-A is Benign according to our data. Variant chr8-33512496-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 437085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTI2	NM_001102401.4	c.118C>T	p.Pro40Ser	missense_variant	2/8	ENST00000431156.7	NP_001095871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTI2	ENST00000431156.7	c.118C>T	p.Pro40Ser	missense_variant	2/8	1	NM_001102401.4	ENSP00000411169	P1

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 758 AN: 152082 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00832

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00472 AC: 1187 AN: 251382 Hom.: 6 AF XY: 0.00480 AC XY: 652 AN XY: 135910

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.00773

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00730 AC: 10668 AN: 1461882 Hom.: 60 Cov.: 34 AF XY: 0.00714 AC XY: 5192 AN XY: 727242

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00871

Gnomad4 OTH exome AF: 0.00628

GnomAD4 genome AF: 0.00499 AC: 759 AN: 152200 Hom.: 1 Cov.: 31 AF XY: 0.00437 AC XY: 325 AN XY: 74398

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00208

Gnomad4 NFE AF: 0.00833

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00702 Hom.: 5

Bravo AF: 0.00522

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00498 AC: 605

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TTI2: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.0078	T;T;T;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T;.;.;T;T
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.38	.;N;N;N;D
REVEL	Benign	0.063
Sift	Benign	0.34	.;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.035	B;B;B;B;.
Vest4		0.076
MVP		0.33
MPC		0.15
ClinPred		0.0094	T
GERP RS		4.4
Varity_R		0.050
gMVP		0.079

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

LitVar

Other links and lift over

dbSNP: rs78781527; hg19: chr8-33370014; COSMIC: COSV100659573; COSMIC: COSV100659573;