15-89623937-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152259.4(TICRR):c.3627C>A(p.Asn1209Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0630

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014027685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.3627C>A	p.Asn1209Lys	missense_variant	20/22	ENST00000268138.12
TICRR	NM_001308025.1	c.3624C>A	p.Asn1208Lys	missense_variant	20/22
KIF7	XM_047432481.1	c.3847+4664G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.3627C>A	p.Asn1209Lys	missense_variant	20/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.3624C>A	p.Asn1208Lys	missense_variant	20/22	1		P4
KIF7	ENST00000558928.1	c.180+4664G>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.0000521 AC: 13 AN: 249692 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135486

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727206

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74474

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0000366 Hom.: 0

Bravo AF: 0.000744

ESP6500AA AF: 0.000938 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000743 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.3627C>A (p.N1209K) alteration is located in exon 20 (coding exon 20) of the TICRR gene. This alteration results from a C to A substitution at nucleotide position 3627, causing the asparagine (N) at amino acid position 1209 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.55
Dann	Benign	0.76
DEOGEN2	Benign	0.0077	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.047
Sift	Benign	0.10	T;T
Sift4G	Benign	0.96	T;T
Polyphen		0.56	P;.
Vest4		0.11
MutPred		0.25		Gain of methylation at N1209 (P = 4e-04);.;
MVP		0.061
MPC		0.065
ClinPred		0.085	T
GERP RS		0.50
Varity_R		0.047
gMVP		0.10

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: rs199746799; hg19: chr15-90167168; COSMIC: COSV51540361; COSMIC: COSV51540361;