15-89608905-T-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.2825T>C(p.Val942Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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=0.20396388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.2825T>C	p.Val942Ala	missense_variant	15/22	ENST00000268138.12
TICRR	NM_001308025.1	c.2822T>C	p.Val941Ala	missense_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.2825T>C	p.Val942Ala	missense_variant	15/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.2822T>C	p.Val941Ala	missense_variant	15/22	1		P4
KIF7	ENST00000558928.1	c.*139A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459044 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Feb 06, 2023

The c.2825T>C (p.V942A) alteration is located in exon 15 (coding exon 15) of the TICRR gene. This alteration results from a T to C substitution at nucleotide position 2825, causing the valine (V) at amino acid position 942 to be replaced by an alanine (A). 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	0.16
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.83	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.26	T;T
Polyphen		0.97	D;.
Vest4		0.26
MutPred		0.14		Loss of stability (P = 0.0907);.;
MVP		0.37
MPC		0.096
ClinPred		0.95	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.24

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: chr15-90152136; COSMIC: COSV51548212;