NM_152259.4:c.3227T>G

Variant names:

• chr15-89621465-T-G
• rs1410447025
• NM_152259.4:c.3227T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152259.4(TICRR):​c.3227T>G​(p.Met1076Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20618737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICRR	NM_152259.4	c.3227T>G	p.Met1076Arg	missense_variant	Exon 19 of 22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.3224T>G	p.Met1075Arg	missense_variant	Exon 19 of 22		NP_001294954.1
KIF7	XM_047432481.1	c.3848-3270A>C		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.3227T>G	p.Met1076Arg	missense_variant	Exon 19 of 22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.3224T>G	p.Met1075Arg	missense_variant	Exon 19 of 22	1		ENSP00000453306.1
KIF7	ENST00000558928.1	n.179-3270A>C		intron_variant	Intron 1 of 2	3		ENSP00000504283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0056	T;.
Eigen	Benign	-0.0049
Eigen_PC	Benign	-0.011
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.12
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.65	T;T
Polyphen		0.92	P;.
Vest4		0.63
MutPred		0.20		Gain of MoRF binding (P = 0.0282);.;
MVP		0.22
MPC		0.054
ClinPred		0.77	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.28

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: rs1410447025; hg19: chr15-90164696;