Genetic Variant NM_001303457.2:c.2761G>A (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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI1	NM_001303457.2	MANE Select	c.2761G>A	p.Asp921Asn	missense	Exon 5 of 8	NP_001290386.1
	TTI1	NM_014657.3		c.2761G>A	p.Asp921Asn	missense	Exon 6 of 9	NP_055472.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTI1	ENST00000373447.8	TSL:1 MANE Select	c.2761G>A	p.Asp921Asn	missense	Exon 5 of 8	ENSP00000362546.3
TTI1	ENST00000373448.6	TSL:1	c.2761G>A	p.Asp921Asn	missense	Exon 6 of 9	ENSP00000362547.2
TTI1	ENST00000449821.1	TSL:2	c.2761G>A	p.Asp921Asn	missense	Exon 4 of 7	ENSP00000407270.1

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 v4.9

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

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.7

PhyloP100

7.2

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

REVEL

Benign

0.18

Sift

Benign

0.041

Sift4G

Uncertain

0.044

Polyphen

0.90

Vest4

0.58

MutPred

0.43

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over