rs1554527020

Variant names:

• chr8-33503883-T-C
• rs1554527020
• NM_001102401.4:c.980A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-33503883-T-C
• chr8-33503883-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001102401.4(TTI2):​c.980A>G​(p.His327Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTI2 NM_001102401.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.840
• Publications: 0 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]

TTI2 Gene-Disease associations (from GenCC):

• severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15481895).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI2	NM_001102401.4	MANE Select	c.980A>G	p.His327Arg	missense	Exon 5 of 8	NP_001095871.1
	TTI2	NM_001265581.2		c.980A>G	p.His327Arg	missense	Exon 5 of 8	NP_001252510.1
	TTI2	NM_025115.5		c.980A>G	p.His327Arg	missense	Exon 4 of 7	NP_079391.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTI2	ENST00000431156.7	TSL:1 MANE Select	c.980A>G	p.His327Arg	missense	Exon 5 of 8	ENSP00000411169.3
	TTI2	ENST00000613904.1	TSL:1	c.980A>G	p.His327Arg	missense	Exon 5 of 8	ENSP00000478396.1
	TTI2	ENST00000360742.9	TSL:2	c.980A>G	p.His327Arg	missense	Exon 4 of 7	ENSP00000353971.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 10, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.84
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.062
Sift	Benign	0.31	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.42		Gain of solvent accessibility (P = 0.039)
MVP		0.48
MPC		0.18
ClinPred		0.098	T
GERP RS		4.6
Varity_R		0.047
gMVP		0.075
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1554527020; hg19: chr8-33361401;