15-89623750-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152259.4(TICRR):ā€‹c.3440C>Gā€‹(p.Pro1147Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 1 hom., cov: 32)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

TICRR
NM_152259.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.09521034).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TICRRNM_152259.4 linkuse as main transcriptc.3440C>G p.Pro1147Arg missense_variant 20/22 ENST00000268138.12 NP_689472.3 Q7Z2Z1-1
TICRRNM_001308025.1 linkuse as main transcriptc.3437C>G p.Pro1146Arg missense_variant 20/22 NP_001294954.1 Q7Z2Z1-2
KIF7XM_047432481.1 linkuse as main transcriptc.3847+4851G>C intron_variant XP_047288437.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TICRRENST00000268138.12 linkuse as main transcriptc.3440C>G p.Pro1147Arg missense_variant 20/225 NM_152259.4 ENSP00000268138.7 Q7Z2Z1-1
TICRRENST00000560985.5 linkuse as main transcriptc.3437C>G p.Pro1146Arg missense_variant 20/221 ENSP00000453306.1 Q7Z2Z1-2
KIF7ENST00000558928.1 linkuse as main transcriptn.178+4851G>C intron_variant 3 ENSP00000504283.1 A0A7I2V527

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152044
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000387
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
249504
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135386
show subpopulations
Gnomad AFR exome
AF:
0.000323
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000894
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:
0.00
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152044
Hom.:
1
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.000387
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000126
Hom.:
0
Bravo
AF:
0.000185
ESP6500AA
AF:
0.00108
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 02, 2022The c.3440C>G (p.P1147R) alteration is located in exon 20 (coding exon 20) of the TICRR gene. This alteration results from a C to G substitution at nucleotide position 3440, causing the proline (P) at amino acid position 1147 to be replaced by an arginine (R). 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
0.11
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.039
T;.
Eigen
Benign
-0.0079
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.50
T;T
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.095
T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.4
M;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Benign
0.088
Sift
Uncertain
0.011
D;D
Sift4G
Uncertain
0.011
D;D
Polyphen
0.96
D;.
Vest4
0.28
MVP
0.27
MPC
0.12
ClinPred
0.45
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.093
gMVP
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200868616; hg19: chr15-90166981; API