20-37996869-G-T

Position:

• chr20-37996869-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001303457.2(TTI1):​c.2878C>A​(p.Leu960Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTI1 NM_001303457.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTI1	NM_001303457.2	c.2878C>A	p.Leu960Ile	missense_variant	6/8	ENST00000373447.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTI1	ENST00000373447.8	c.2878C>A	p.Leu960Ile	missense_variant	6/8	1	NM_001303457.2	P1
TTI1	ENST00000373448.6	c.2878C>A	p.Leu960Ile	missense_variant	7/9	1		P1
TTI1	ENST00000449821.1	c.2878C>A	p.Leu960Ile	missense_variant	5/7	2		P1
TTI1	ENST00000473288.1	n.337C>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.2878C>A (p.L960I) alteration is located in exon 7 (coding exon 5) of the TTI1 gene. This alteration results from a C to A substitution at nucleotide position 2878, causing the leucine (L) at amino acid position 960 to be replaced by an isoleucine (I). 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	0.32
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T;T;T
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.9	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.65
MutPred		0.74		Gain of methylation at K955 (P = 0.047);Gain of methylation at K955 (P = 0.047);Gain of methylation at K955 (P = 0.047);
MVP		0.41
MPC		0.65
ClinPred		0.97	D
GERP RS		-0.93
Varity_R		0.45
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-36625271;