15-89623773-G-A

Position:

• chr15-89623773-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152259.4(TICRR):​c.3463G>A​(p.Glu1155Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1155D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.521

Genes affected

TICRR (HGNC:28704): (TOPBP1 interacting checkpoint and replication regulator) Enables chromatin binding activity. Involved in regulation of DNA-dependent DNA replication initiation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

KIF7 (HGNC:30497): (kinesin family member 7) This gene encodes a cilia-associated protein belonging to the kinesin family. This protein plays a role in the sonic hedgehog (SHH) signaling pathway through the regulation of GLI transcription factors. It functions as a negative regulator of the SHH pathway by preventing inappropriate activation of GLI2 in the absence of ligand, and as a positive regulator by preventing the processing of GLI3 into its repressor form. Mutations in this gene have been associated with various ciliopathies. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039459646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICRR	NM_152259.4	c.3463G>A	p.Glu1155Lys	missense_variant	20/22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.3460G>A	p.Glu1154Lys	missense_variant	20/22		NP_001294954.1
KIF7	XM_047432481.1	c.3847+4828C>T		intron_variant			XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.3463G>A	p.Glu1155Lys	missense_variant	20/22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.3460G>A	p.Glu1154Lys	missense_variant	20/22	1		ENSP00000453306.1
KIF7	ENST00000558928.1	n.178+4828C>T		intron_variant		3		ENSP00000504283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.3463G>A (p.E1155K) alteration is located in exon 20 (coding exon 20) of the TICRR gene. This alteration results from a G to A substitution at nucleotide position 3463, causing the glutamic acid (E) at amino acid position 1155 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.2
DANN	Benign	0.75
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.032
Sift	Benign	0.67	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0010	B;.
Vest4		0.061
MutPred		0.22		Gain of MoRF binding (P = 0.0039);.;
MVP		0.081
MPC		0.026
ClinPred		0.023	T
GERP RS		0.34
Varity_R		0.043
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-90167004;