rs398122367

Variant names:

• chr8-33500443-A-T
• rs398122367
• NM_001102401.4:c.1307T>A
• TTI2 p.Ile436Asn

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.65
• Publications: 8 publications found

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]

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]

ACMG classification

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

Sel.	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

Sel.	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.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.31
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.37
gMVP		0.58
Mutation Taster		=6/94	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398122367;

hg19: chr8-33357961;