rs3743372

Positions:

• chr15-89627006-C-A
• chr15-89627006-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152259.4(TICRR):​c.5653C>A​(p.Arg1885Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1885C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08742958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICRR	NM_152259.4	c.5653C>A	p.Arg1885Ser	missense_variant	22/22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.5650C>A	p.Arg1884Ser	missense_variant	22/22		NP_001294954.1
KIF7	XM_047432481.1	c.3847+1595G>T		intron_variant			XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.5653C>A	p.Arg1885Ser	missense_variant	22/22	5	NM_152259.4	ENSP00000268138	A2
TICRR	ENST00000560985.5	c.5650C>A	p.Arg1884Ser	missense_variant	22/22	1		ENSP00000453306	P4
TICRR	ENST00000561095.1	c.565C>A	p.Arg189Ser	missense_variant, NMD_transcript_variant	3/4	1		ENSP00000453922
KIF7	ENST00000558928.1	c.180+1595G>T		intron_variant, NMD_transcript_variant		3		ENSP00000504283

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0031	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.053
Sift	Benign	0.30	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.25	B;.
Vest4		0.13
MutPred		0.24		Loss of solvent accessibility (P = 0.0017);.;
MVP		0.18
MPC		0.042
ClinPred		0.22	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743372; hg19: chr15-90170237; COSMIC: COSV51538018; COSMIC: COSV51538018;