Genetic Variant NM_001303457.2:c.2761G>T (chr20-37999220-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001303457.2(TTI1):c.2761G>T(p.Asp921Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000012 in 1,505,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TTI1
NM_001303457.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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>T	p.Asp921Tyr	missense	Exon 5 of 8	NP_001290386.1
	TTI1	NM_014657.3		c.2761G>T	p.Asp921Tyr	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>T	p.Asp921Tyr	missense	Exon 5 of 8	ENSP00000362546.3
TTI1	ENST00000373448.6	TSL:1	c.2761G>T	p.Asp921Tyr	missense	Exon 6 of 9	ENSP00000362547.2
TTI1	ENST00000449821.1	TSL:2	c.2761G>T	p.Asp921Tyr	missense	Exon 4 of 7	ENSP00000407270.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181054

AF XY:

0.0000102

show subpopulations

Gnomad AFR exome

AF:

0.0000803

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:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000126

AC:

AN:

1353006

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

670034

show subpopulations

African (AFR)

AF:

0.0000692

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:

0.0000142

AC:

AN:

1056766

Other (OTH)

AF:

0.00

AC:

AN:

55292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.4

PhyloP100

7.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.41

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.81

MVP

0.71

MPC

0.68

ClinPred

0.95

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.43

gMVP

0.53

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.91

Position offset: 2

DS_DL_spliceai

0.24

Position offset: -32

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over