15-89624877-C-T

Position:

• chr15-89624877-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152259.4(TICRR):​c.4567C>T​(p.Arg1523Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 1,614,006 control chromosomes in the GnomAD database, including 650,231 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1523H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.90 (61860 hom., cov: 31)
  • Exomes 𝑓: 0.90 (588371 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.751646E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.4567C>T	p.Arg1523Cys	missense_variant	20/22	ENST00000268138.12
TICRR	NM_001308025.1	c.4564C>T	p.Arg1522Cys	missense_variant	20/22
KIF7	XM_047432481.1	c.3847+3724G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.4567C>T	p.Arg1523Cys	missense_variant	20/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.4564C>T	p.Arg1522Cys	missense_variant	20/22	1		P4
KIF7	ENST00000558928.1	c.180+3724G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136735 AN: 152052 Hom.: 61807 Cov.: 31

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.889

GnomAD3 exomes AF: 0.859 AC: 215376 AN: 250648 Hom.: 93572 AF XY: 0.864 AC XY: 117059 AN XY: 135486

Gnomad AFR exome AF: 0.964

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.841

Gnomad EAS exome AF: 0.679

Gnomad SAS exome AF: 0.861

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.911

Gnomad OTH exome AF: 0.872

GnomAD4 exome AF: 0.895 AC: 1308790 AN: 1461836 Hom.: 588371 Cov.: 69 AF XY: 0.895 AC XY: 650916 AN XY: 727212

Gnomad4 AFR exome AF: 0.962

Gnomad4 AMR exome AF: 0.731

Gnomad4 ASJ exome AF: 0.847

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.868

Gnomad4 FIN exome AF: 0.885

Gnomad4 NFE exome AF: 0.913

Gnomad4 OTH exome AF: 0.889

GnomAD4 genome AF: 0.899 AC: 136845 AN: 152170 Hom.: 61860 Cov.: 31 AF XY: 0.895 AC XY: 66545 AN XY: 74386

Gnomad4 AFR AF: 0.959

Gnomad4 AMR AF: 0.793

Gnomad4 ASJ AF: 0.833

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.843

Gnomad4 FIN AF: 0.887

Gnomad4 NFE AF: 0.912

Gnomad4 OTH AF: 0.885

Alfa AF: 0.901 Hom.: 128497

Bravo AF: 0.892

TwinsUK AF: 0.909 AC: 3370

ALSPAC AF: 0.915 AC: 3526

ESP6500AA AF: 0.961 AC: 4228

ESP6500EA AF: 0.906 AC: 7792

ExAC AF: 0.868 AC: 105338

Asia WGS AF: 0.773 AC: 2691 AN: 3478

EpiCase AF: 0.907

EpiControl AF: 0.905

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.48
DEOGEN2	Benign	0.0042	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	7.8e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.78	N;N
REVEL	Benign	0.079
Sift	Benign	0.24	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;.
Vest4		0.13
MPC		0.029
ClinPred		0.0084	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.31

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: rs894157; hg19: chr15-90168108; COSMIC: COSV51539417; COSMIC: COSV51539417;