chr20-37996869-G-T

Variant names:

• chr20-37996869-G-T
• NM_001303457.2:c.2878C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly and movement abnormalities

  Inheritance: AR Classification: STRONG Submitted by: Broad Center for Mendelian Genomics
• microcephaly

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303457.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI1	NM_001303457.2	MANE Select	c.2878C>A	p.Leu960Ile	missense	Exon 6 of 8	NP_001290386.1	O43156
	TTI1	NM_014657.3		c.2878C>A	p.Leu960Ile	missense	Exon 7 of 9	NP_055472.1	O43156

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI1	ENST00000373447.8	TSL:1 MANE Select	c.2878C>A	p.Leu960Ile	missense	Exon 6 of 8	ENSP00000362546.3	O43156
	TTI1	ENST00000373448.6	TSL:1	c.2878C>A	p.Leu960Ile	missense	Exon 7 of 9	ENSP00000362547.2	O43156
	TTI1	ENST00000898963.1		c.2932C>A	p.Leu978Ile	missense	Exon 6 of 8	ENSP00000569022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.74		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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr20-36625271;