15-89623800-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.3490G>A(p.Gly1164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.317

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=0.034685165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.3490G>A	p.Gly1164Ser	missense_variant	20/22	ENST00000268138.12
TICRR	NM_001308025.1	c.3487G>A	p.Gly1163Ser	missense_variant	20/22
KIF7	XM_047432481.1	c.3847+4801C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.3490G>A	p.Gly1164Ser	missense_variant	20/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.3487G>A	p.Gly1163Ser	missense_variant	20/22	1		P4
KIF7	ENST00000558928.1	c.180+4801C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151866 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249078 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151866 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74204

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Aug 09, 2021

The c.3490G>A (p.G1164S) 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 3490, causing the glycine (G) at amino acid position 1164 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.097
Dann	Benign	0.48
DEOGEN2	Benign	0.0018	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.18	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.0030
Sift	Benign	0.54	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.032	B;.
Vest4		0.042
MutPred		0.15		Gain of phosphorylation at G1164 (P = 0.0027);.;
MVP		0.030
MPC		0.025
ClinPred		0.0078	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs751912896; hg19: chr15-90167031; COSMIC: COSV51542955; COSMIC: COSV51542955;