dbSNP rs398122367: TTI2:p.Ile436Asn (chr8-33500443-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001102401.4(TTI2):c.1307T>A(p.Ile436Asn) variant causes a missense change. 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

TTI2
NM_001102401.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.65

Publications

8 publications found

Variant links:

Genes affected

TTI2 (HGNC:26262): (TELO2 interacting protein 2) This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]

TTI2 links:

MAK16 (HGNC:13703): (MAK16 homolog) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA and maturation of LSU-rRNA. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

MAK16 links:

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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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

PP5

Variant 8-33500443-A-T is Pathogenic according to our data. Variant chr8-33500443-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 88868.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102401.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTI2	NM_001102401.4	MANE Select	c.1307T>A	p.Ile436Asn	missense	Exon 7 of 8	NP_001095871.1	Q6NXR4
MAK16	NM_032509.4	MANE Select	c.*1814A>T		3_prime_UTR	Exon 10 of 10	NP_115898.2
TTI2	NM_001265581.2		c.1307T>A	p.Ile436Asn	missense	Exon 7 of 8	NP_001252510.1	Q6NXR4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTI2	ENST00000431156.7	TSL:1 MANE Select	c.1307T>A	p.Ile436Asn	missense	Exon 7 of 8	ENSP00000411169.3	Q6NXR4
TTI2	ENST00000613904.1	TSL:1	c.1307T>A	p.Ile436Asn	missense	Exon 7 of 8	ENSP00000478396.1	Q6NXR4
MAK16	ENST00000360128.11	TSL:1 MANE Select	c.*1814A>T		3_prime_UTR	Exon 10 of 10	ENSP00000353246.5	Q9BXY0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

0.010

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.085

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

PhyloP100

6.6

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.31

Sift

Benign

0.032

Sift4G

Uncertain

0.0020

Polyphen

0.87

Vest4

0.91

MutPred

0.55

Loss of helix (P = 0.0068)

MVP

0.69

MPC

0.59

ClinPred

0.94

GERP RS

5.2

Varity_R

0.37

gMVP

0.58

Mutation Taster

=6/94

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

Computational scores

Splicing

Publications

Other links and lift over