chr15-89624877-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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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	Protein	UniProt
TICRR	NM_152259.4	c.4567C>T	p.Arg1523Cys	missense_variant	20/22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.4564C>T	p.Arg1522Cys	missense_variant	20/22		NP_001294954.1
KIF7	XM_047432481.1	c.3847+3724G>A		intron_variant			XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.4567C>T	p.Arg1523Cys	missense_variant	20/22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.4564C>T	p.Arg1522Cys	missense_variant	20/22	1		ENSP00000453306.1
KIF7	ENST00000558928.1	n.178+3724G>A		intron_variant		3		ENSP00000504283.1

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;.
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;