rs3736497

chr8-33500476-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001102401.4(TTI2):c.1274T>G(p.Leu425Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000337 in 1,614,162 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: TTI2 NM_001102401.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.92

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008345276).
• BP6: Variant 8-33500476-A-C is Benign according to our data. Variant chr8-33500476-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437080.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTI2	NM_001102401.4	c.1274T>G	p.Leu425Arg	missense_variant	7/8	ENST00000431156.7
MAK16	NM_032509.4	c.*1847A>C		3_prime_UTR_variant	10/10	ENST00000360128.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTI2	ENST00000431156.7	c.1274T>G	p.Leu425Arg	missense_variant	7/8	1	NM_001102401.4	P1
MAK16	ENST00000360128.11	c.*1847A>C		3_prime_UTR_variant	10/10	1	NM_032509.4	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00903

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000597 AC: 150 AN: 251372 Hom.: 0 AF XY: 0.000589 AC XY: 80 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00756

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1461830 Hom.: 2 Cov.: 31 AF XY: 0.000330 AC XY: 240 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00905

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000414 Hom.: 1

Bravo AF: 0.000317

ExAC AF: 0.000610 AC: 74

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 01, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.020	T;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T;.;.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0083	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.055	B;B;B;B
Vest4		0.41
MutPred		0.24		Gain of methylation at L425 (P = 0.0312);Gain of methylation at L425 (P = 0.0312);Gain of methylation at L425 (P = 0.0312);.;
MVP		0.66
MPC		0.24
ClinPred		0.050	T
GERP RS		3.0
Varity_R		0.23
gMVP		0.51

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: rs3736497; hg19: chr8-33357994; COSMIC: COSV62452174; COSMIC: COSV62452174;