15-89624877-C-T

Variant names:

• chr15-89624877-C-T
• rs894157
• NM_152259.4:c.4567C>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.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. 15/21 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. 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
• Publications: 32 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=7.751646E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152259.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICRR	NM_152259.4	MANE Select	c.4567C>T	p.Arg1523Cys	missense	Exon 20 of 22	NP_689472.3
	TICRR	NM_001308025.1		c.4564C>T	p.Arg1522Cys	missense	Exon 20 of 22	NP_001294954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICRR	ENST00000268138.12	TSL:5 MANE Select	c.4567C>T	p.Arg1523Cys	missense	Exon 20 of 22	ENSP00000268138.7
	TICRR	ENST00000560985.5	TSL:1	c.4564C>T	p.Arg1522Cys	missense	Exon 20 of 22	ENSP00000453306.1
	KIF7	ENST00000558928.1	TSL:3	n.178+3724G>A		intron	N/A	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

GnomAD2 exomes AF: 0.859 AC: 215376 AN: 250648 AF XY: 0.864

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 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

African (AFR) AF: 0.962 AC: 32196 AN: 33480

American (AMR) AF: 0.731 AC: 32676 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 22142 AN: 26132

East Asian (EAS) AF: 0.645 AC: 25600 AN: 39700

South Asian (SAS) AF: 0.868 AC: 74891 AN: 86256

European-Finnish (FIN) AF: 0.885 AC: 47233 AN: 53382

Middle Eastern (MID) AF: 0.872 AC: 5029 AN: 5768

European-Non Finnish (NFE) AF: 0.913 AC: 1015323 AN: 1112000

Other (OTH) AF: 0.889 AC: 53700 AN: 60394

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

African (AFR) AF: 0.959 AC: 39831 AN: 41530

American (AMR) AF: 0.793 AC: 12113 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2890 AN: 3470

East Asian (EAS) AF: 0.682 AC: 3510 AN: 5150

South Asian (SAS) AF: 0.843 AC: 4061 AN: 4818

European-Finnish (FIN) AF: 0.887 AC: 9398 AN: 10592

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.912 AC: 62043 AN: 68006

Other (OTH) AF: 0.885 AC: 1871 AN: 2114

Alfa AF: 0.903 Hom.: 179415

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 v4.9

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
MetaRNN	Benign	7.8e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		3.0
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.079
Sift	Benign	0.24	T
Sift4G	Benign	0.14	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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