NM_152259.4:c.5653C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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 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
• Publications: 34 publications found

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]

KIF7 Gene-Disease associations (from GenCC):

• acrocallosal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hydrolethalus syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hydrolethalus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• multiple epiphyseal dysplasia, Al-Gazali type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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

GnomAD2 exomes AF: 0.307 AC: 77235 AN: 251460 AF XY: 0.316

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 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

African (AFR) AF: 0.0731 AC: 2446 AN: 33480

American (AMR) AF: 0.284 AC: 12681 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7943 AN: 26132

East Asian (EAS) AF: 0.340 AC: 13508 AN: 39694

South Asian (SAS) AF: 0.370 AC: 31946 AN: 86246

European-Finnish (FIN) AF: 0.277 AC: 14805 AN: 53380

Middle Eastern (MID) AF: 0.378 AC: 2180 AN: 5768

European-Non Finnish (NFE) AF: 0.331 AC: 367488 AN: 1111838

Other (OTH) AF: 0.324 AC: 19543 AN: 60384

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

African (AFR) AF: 0.0891 AC: 3701 AN: 41520

American (AMR) AF: 0.281 AC: 4295 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1032 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1778 AN: 5154

South Asian (SAS) AF: 0.371 AC: 1783 AN: 4808

European-Finnish (FIN) AF: 0.275 AC: 2910 AN: 10590

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22504 AN: 67952

Other (OTH) AF: 0.286 AC: 602 AN: 2108

Alfa AF: 0.305 Hom.: 25308

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;.
PhyloP100		1.0
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3743372; hg19: chr15-90170237; COSMIC: COSV51541582; COSMIC: COSV51541582;