chr20-37996947-G-A

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

19

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]

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
TTI1NM_001303457.2 linkuse as main transcriptc.2800C>T p.Arg934Cys missense_variant 6/8 ENST00000373447.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTI1ENST00000373447.8 linkuse as main transcriptc.2800C>T p.Arg934Cys missense_variant 6/81 NM_001303457.2 P1
TTI1ENST00000373448.6 linkuse as main transcriptc.2800C>T p.Arg934Cys missense_variant 7/91 P1
TTI1ENST00000449821.1 linkuse as main transcriptc.2800C>T p.Arg934Cys missense_variant 5/72 P1
TTI1ENST00000473288.1 linkuse as main transcriptn.259C>T non_coding_transcript_exon_variant 3/45

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152150
Hom.:
0
Cov.:
32
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:
10
AN:
250242
Hom.:
0
AF XY:
0.0000517
AC XY:
7
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:
24
AN:
1461046
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
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:
3
AN:
152268
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
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:
7
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 submitterclinical testingAmbry GeneticsMay 10, 2024The 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
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
13
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
D
LIST_S2
Benign
0.81
.;.;T
M_CAP
Benign
0.0098
T
MetaRNN
Benign
0.018
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-2.4
N;N;N
MutationTaster
Benign
0.93
N;N;N
PrimateAI
Benign
0.21
T
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
T
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.

Other links and lift over

dbSNP: rs575066309; hg19: chr20-36625349; COSMIC: COSV65063391; API