15-89619775-C-G

Variant names:

• chr15-89619775-C-G
• NM_152259.4:c.3087C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152259.4(TICRR):​c.3087C>G​(p.Phe1029Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICRR	NM_152259.4	c.3087C>G	p.Phe1029Leu	missense_variant	Exon 18 of 22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.3084C>G	p.Phe1028Leu	missense_variant	Exon 18 of 22		NP_001294954.1
KIF7	XM_047432481.1	c.3848-1580G>C		intron_variant	Intron 19 of 19		XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.3087C>G	p.Phe1029Leu	missense_variant	Exon 18 of 22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.3084C>G	p.Phe1028Leu	missense_variant	Exon 18 of 22	1		ENSP00000453306.1
KIF7	ENST00000558928.1	n.179-1580G>C		intron_variant	Intron 1 of 2	3		ENSP00000504283.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461726 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727168

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3087C>G (p.F1029L) alteration is located in exon 18 (coding exon 18) of the TICRR gene. This alteration results from a C to G substitution at nucleotide position 3087, causing the phenylalanine (F) at amino acid position 1029 to be replaced by a leucine (L). 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	Pathogenic	0.87
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;.
Vest4		0.60
MutPred		0.14		Gain of MoRF binding (P = 0.1817);.;
MVP		0.40
MPC		0.21
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.35

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: chr15-90163006;