15-89608848-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152259.4(TICRR):c.2768C>G(p.Ser923Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,606,920 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (23 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.81

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008205891).
• BP6: Variant 15-89608848-C-G is Benign according to our data. Variant chr15-89608848-C-G is described in ClinVar as [Benign]. Clinvar id is 789825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1527/152126) while in subpopulation AFR AF= 0.0349 (1447/41484). AF 95% confidence interval is 0.0334. There are 27 homozygotes in gnomad4. There are 739 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.2768C>G	p.Ser923Cys	missense_variant	15/22	ENST00000268138.12
TICRR	NM_001308025.1	c.2765C>G	p.Ser922Cys	missense_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.2768C>G	p.Ser923Cys	missense_variant	15/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.2765C>G	p.Ser922Cys	missense_variant	15/22	1		P4
KIF7	ENST00000558928.1	c.*196G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1523 AN: 152008 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

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: 0.000206

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00224 AC: 541 AN: 242044 Hom.: 4 AF XY: 0.00164 AC XY: 216 AN XY: 131674

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000632

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000946 AC: 1376 AN: 1454794 Hom.: 23 Cov.: 31 AF XY: 0.000818 AC XY: 592 AN XY: 723730

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000470

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.0100 AC: 1527 AN: 152126 Hom.: 27 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74390

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00138 Hom.: 2

Bravo AF: 0.0115

ESP6500AA AF: 0.0328 AC: 120

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00298 AC: 360

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.56
MVP		0.46
MPC		0.20
ClinPred		0.023	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.44

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: rs16943377; hg19: chr15-90152079;