rs398122367

Positions:

• chr8-33500443-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 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 id is 88868.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-33500443-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTI2	NM_001102401.4	c.1307T>A	p.Ile436Asn	missense_variant	7/8	ENST00000431156.7	NP_001095871.1
MAK16	NM_032509.4	c.*1814A>T		3_prime_UTR_variant	10/10	ENST00000360128.11	NP_115898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTI2	ENST00000431156.7	c.1307T>A	p.Ile436Asn	missense_variant	7/8	1	NM_001102401.4	ENSP00000411169	P1
MAK16	ENST00000360128.11	c.*1814A>T		3_prime_UTR_variant	10/10	1	NM_032509.4	ENSP00000353246	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;.;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	.;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.032	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.87	P;P;P;P
Vest4		0.91
MutPred		0.55		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;
MVP		0.69
MPC		0.59
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs398122367; hg19: chr8-33357961;