chr15-89623630-A-C

Position:

• chr15-89623630-A-C

Variant summary

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

The NM_152259.4(TICRR):​c.3320A>C​(p.Lys1107Thr) 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. 13/21 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)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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=0.14045724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICRR	NM_152259.4	c.3320A>C	p.Lys1107Thr	missense_variant	20/22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.3317A>C	p.Lys1106Thr	missense_variant	20/22		NP_001294954.1
KIF7	XM_047432481.1	c.3847+4971T>G		intron_variant			XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.3320A>C	p.Lys1107Thr	missense_variant	20/22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.3317A>C	p.Lys1106Thr	missense_variant	20/22	1		ENSP00000453306.1
KIF7	ENST00000558928.1	n.178+4971T>G		intron_variant		3		ENSP00000504283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Dec 14, 2023

The c.3320A>C (p.K1107T) alteration is located in exon 20 (coding exon 20) of the TICRR gene. This alteration results from a A to C substitution at nucleotide position 3320, causing the lysine (K) at amino acid position 1107 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.069
Sift	Benign	0.049	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.81	P;.
Vest4		0.21
MutPred		0.23		Loss of methylation at K1107 (P = 0.0093);.;
MVP		0.18
MPC		0.19
ClinPred		0.77	D
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.052
gMVP		0.12

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: chr15-90166861;