Genetic Variant TTI1:p.Asp921Asn (chr20-37999220-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001303457.2(TTI1):c.2761G>A(p.Asp921Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D921G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTI1
NM_001303457.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.16

Publications

2 publications found

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 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

TTI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-37999220-C-T is Pathogenic according to our data. Variant chr20-37999220-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402171.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTI1	NM_001303457.2 link	c.2761G>A	p.Asp921Asn	missense_variant	Exon 5 of 8	ENST00000373447.8	NP_001290386.1	O43156

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTI1	ENST00000373447.8 link	c.2761G>A	p.Asp921Asn	missense_variant	Exon 5 of 8	1	NM_001303457.2	ENSP00000362546.3	O43156
TTI1	ENST00000373448.6 link	c.2761G>A	p.Asp921Asn	missense_variant	Exon 6 of 9	1		ENSP00000362547.2	O43156
TTI1	ENST00000449821.1 link	c.2761G>A	p.Asp921Asn	missense_variant	Exon 4 of 7	2		ENSP00000407270.1	O43156
TTI1	ENST00000473288.1 link	n.220G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1353006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670034

African (AFR)

AF:

0.00

AC:

AN:

28914

American (AMR)

AF:

0.00

AC:

AN:

29770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22164

East Asian (EAS)

AF:

0.00

AC:

AN:

34080

South Asian (SAS)

AF:

0.00

AC:

AN:

69706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1056766

Other (OTH)

AF:

0.00

AC:

AN:

55292

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Neurodevelopmental disorder with microcephaly and movement abnormalities

Pathogenic:1

Jul 21, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;.;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

7.2

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.041

D;D;D

Sift4G

Uncertain

0.044

D;D;D

Polyphen

0.90

P;P;P

Vest4

0.58

MutPred

0.43

Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);

MVP

0.55

MPC

0.59

ClinPred

0.90

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.14

gMVP

0.29

Mutation Taster

=73/27

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over