Variant chr20-37996947-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001303457.2(TTI1):c.2800C>T(p.Arg934Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R934H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TTI1
NM_001303457.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018469602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTI1	NM_001303457.2 linkuse as main transcript	c.2800C>T	p.Arg934Cys	missense_variant	6/8	ENST00000373447.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TTI1	ENST00000373447.8 linkuse as main transcript	c.2800C>T	p.Arg934Cys	missense_variant	6/8	1	NM_001303457.2	P1
TTI1	ENST00000373448.6 linkuse as main transcript	c.2800C>T	p.Arg934Cys	missense_variant	7/9	1		P1
TTI1	ENST00000449821.1 linkuse as main transcript	c.2800C>T	p.Arg934Cys	missense_variant	5/7	2		P1
TTI1	ENST00000473288.1 linkuse as main transcript	n.259C>T		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250242

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461046

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726708

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The c.2800C>T (p.R934C) alteration is located in exon 7 (coding exon 5) of the TTI1 gene. This alteration results from a C to T substitution at nucleotide position 2800, causing the arginine (R) at amino acid position 934 to be replaced by a cysteine (C). 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

0.074

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.013

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.81

.;.;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.4

N;N;N

MutationTaster

Benign

0.93

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

4.8

N;N;N

REVEL

Benign

0.089

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.12

MutPred

0.43

Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);Loss of MoRF binding (P = 0.0141);

MVP

0.35

MPC

0.19

ClinPred

0.029

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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