rs1232246210

Variant names:

• chr15-89621425-C-G
• rs1232246210
• NM_152259.4:c.3187C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-89621425-C-G
• chr15-89621425-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152259.4(TICRR):​c.3187C>G​(p.Arg1063Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1063L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• Publications: 3 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• neurodevelopmental disorder

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

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22502765).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICRR	NM_152259.4	MANE Select	c.3187C>G	p.Arg1063Gly	missense	Exon 19 of 22	NP_689472.3
	TICRR	NM_001308025.1		c.3184C>G	p.Arg1062Gly	missense	Exon 19 of 22	NP_001294954.1	Q7Z2Z1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICRR	ENST00000268138.12	TSL:5 MANE Select	c.3187C>G	p.Arg1063Gly	missense	Exon 19 of 22	ENSP00000268138.7	Q7Z2Z1-1
	TICRR	ENST00000560985.5	TSL:1	c.3184C>G	p.Arg1062Gly	missense	Exon 19 of 22	ENSP00000453306.1	Q7Z2Z1-2
	TICRR	ENST00000929580.1		c.3187C>G	p.Arg1063Gly	missense	Exon 19 of 21	ENSP00000599639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 245880 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000600

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458272 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725348

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.0000459 AC: 2 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111128

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.6
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.051
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.041	D
Polyphen		0.76	P
Vest4		0.37
MutPred		0.20		Loss of MoRF binding (P = 0.0181)
MVP		0.29
MPC		0.055
ClinPred		0.87	D
GERP RS		3.7
Varity_R		0.13
gMVP		0.14

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: rs1232246210; hg19: chr15-90164656;