Genetic Variant TTI1:p.Glu1048Lys (chr20-37983584-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001303457.2(TTI1):c.3142G>A(p.Glu1048Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000774 in 1,421,950 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

TTI1
NM_001303457.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Variant links:

Genes affected

TTI1 (HGNC:29029): (TELO2 interacting protein 1) Involved in regulation of TOR signaling. Located in cytoplasm. Part of TORC1 complex and TORC2 complex. [provided by Alliance of Genome Resources, Apr 2022]

TTI1 links:

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 rank	MANE	Protein	UniProt
TTI1	NM_001303457.2 link	c.3142G>A	p.Glu1048Lys	missense_variant	Exon 8 of 8	ENST00000373447.8	NP_001290386.1	O43156
TTI1	NM_014657.3 link	c.3142G>A	p.Glu1048Lys	missense_variant	Exon 9 of 9		NP_055472.1	O43156
TTI1	XM_047440606.1 link	c.3142G>A	p.Glu1048Lys	missense_variant	Exon 8 of 8		XP_047296562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTI1	ENST00000373447.8 link	c.3142G>A	p.Glu1048Lys	missense_variant	Exon 8 of 8	1	NM_001303457.2	ENSP00000362546.3	O43156
TTI1	ENST00000373448.6 link	c.3142G>A	p.Glu1048Lys	missense_variant	Exon 9 of 9	1		ENSP00000362547.2	O43156
TTI1	ENST00000449821.1 link	c.3142G>A	p.Glu1048Lys	missense_variant	Exon 7 of 7	2		ENSP00000407270.1	O43156

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000141

AC:

AN:

213048

Hom.:

AF XY:

0.0000261

AC XY:

AN XY:

114986

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000307

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000774

AC:

AN:

1421950

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

703886

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000732

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3142G>A (p.E1048K) alteration is located in exon 9 (coding exon 7) of the TTI1 gene. This alteration results from a G to A substitution at nucleotide position 3142, causing the glutamic acid (E) at amino acid position 1048 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.93

.;.;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.29

Sift

Uncertain

0.020

D;D;D

Sift4G

Uncertain

0.034

D;D;D

Polyphen

0.73

P;P;P

Vest4

0.52

MVP

0.69

MPC

0.30

ClinPred

0.87

GERP RS

2.3

Varity_R

0.12

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over