15-89627006-C-T

Variant names:

• chr15-89627006-C-T
• rs3743372
• NM_152259.4:c.5653C>T

Variant summary

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

The NM_152259.4(TICRR):​c.5653C>T​(p.Arg1885Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,613,722 control chromosomes in the GnomAD database, including 84,109 homozygotes. In-silico tool predicts 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1885H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5897 hom., cov: 32)
  • Exomes 𝑓: 0.32 (78212 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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=0.0045485795).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICRR	NM_152259.4	c.5653C>T	p.Arg1885Cys	missense_variant	Exon 22 of 22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.5650C>T	p.Arg1884Cys	missense_variant	Exon 22 of 22		NP_001294954.1
KIF7	XM_047432481.1	c.3847+1595G>A		intron_variant	Intron 19 of 19		XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.5653C>T	p.Arg1885Cys	missense_variant	Exon 22 of 22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.5650C>T	p.Arg1884Cys	missense_variant	Exon 22 of 22	1		ENSP00000453306.1
TICRR	ENST00000561095.1	n.562C>T		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000453922.1
KIF7	ENST00000558928.1	n.178+1595G>A		intron_variant	Intron 1 of 2	3		ENSP00000504283.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39006 AN: 151960 Hom.: 5897 Cov.: 32

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.307 AC: 77235 AN: 251460 Hom.: 12633 AF XY: 0.316 AC XY: 42931 AN XY: 135904

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.356

Gnomad SAS exome AF: 0.368

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.323 AC: 472540 AN: 1461644 Hom.: 78212 Cov.: 36 AF XY: 0.326 AC XY: 237196 AN XY: 727130

Gnomad4 AFR exome AF: 0.0731

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.370

Gnomad4 FIN exome AF: 0.277

Gnomad4 NFE exome AF: 0.331

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.256 AC: 38999 AN: 152078 Hom.: 5897 Cov.: 32 AF XY: 0.258 AC XY: 19158 AN XY: 74332

Gnomad4 AFR AF: 0.0891

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.286

Alfa AF: 0.315 Hom.: 19192

Bravo AF: 0.246

TwinsUK AF: 0.328 AC: 1216

ALSPAC AF: 0.336 AC: 1295

ESP6500AA AF: 0.0864 AC: 380

ESP6500EA AF: 0.334 AC: 2873

ExAC AF: 0.302 AC: 36652

Asia WGS AF: 0.327 AC: 1136 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.339

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0076	T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.068
Sift	Benign	0.035	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.18
MPC		0.16
ClinPred		0.023	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3743372; hg19: chr15-90170237; COSMIC: COSV51541582; COSMIC: COSV51541582;