NM_001303457.2:c.3102G>C

Variant names:

• chr20-37983624-C-G
• rs143008653
• NM_001303457.2:c.3102G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_001303457.2(TTI1):​c.3102G>C​(p.Leu1034Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000535 in 1,532,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: TTI1 NM_001303457.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40340424).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000526 (8/152154) while in subpopulation NFE AF = 0.000118 (8/68020). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.3102G>C	p.Leu1034Phe	missense	Exon 8 of 8	NP_001290386.1	O43156
	TTI1	NM_014657.3		c.3102G>C	p.Leu1034Phe	missense	Exon 9 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.3102G>C	p.Leu1034Phe	missense	Exon 8 of 8	ENSP00000362546.3	O43156
	TTI1	ENST00000373448.6	TSL:1	c.3102G>C	p.Leu1034Phe	missense	Exon 9 of 9	ENSP00000362547.2	O43156
	TTI1	ENST00000898963.1		c.3156G>C	p.Leu1052Phe	missense	Exon 8 of 8	ENSP00000569022.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000329 AC: 6 AN: 182646 AF XY: 0.0000308

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000590

Gnomad OTH exome AF: 0.000239

GnomAD4 exome AF: 0.0000536 AC: 74 AN: 1380646 Hom.: 0 Cov.: 30 AF XY: 0.0000457 AC XY: 31 AN XY: 678396

African (AFR) AF: 0.00 AC: 0 AN: 30684

American (AMR) AF: 0.00 AC: 0 AN: 34558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36730

South Asian (SAS) AF: 0.00 AC: 0 AN: 74076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5404

European-Non Finnish (NFE) AF: 0.0000691 AC: 74 AN: 1070514

Other (OTH) AF: 0.00 AC: 0 AN: 56780

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000248 AC: 3

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	0.24
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.50
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.89	P
Vest4		0.50
MutPred		0.54		Gain of sheet (P = 0.0477)
MVP		0.79
MPC		0.29
ClinPred		0.23	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.54
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs143008653; hg19: chr20-36612026;