15-89582890-C-T

Variant names:

• chr15-89582890-C-T
• rs10775247
• NM_152259.4:c.859C>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.859C>T​(p.Arg287Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,613,896 control chromosomes in the GnomAD database, including 248,398 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. R287H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (18382 hom., cov: 33)
  • Exomes 𝑓: 0.56 (230016 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436
• Publications: 37 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]

ENSG00000259713 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.037585E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICRR	NM_152259.4	c.859C>T	p.Arg287Cys	missense_variant	Exon 2 of 22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.859C>T	p.Arg287Cys	missense_variant	Exon 2 of 22		NP_001294954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.859C>T	p.Arg287Cys	missense_variant	Exon 2 of 22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.859C>T	p.Arg287Cys	missense_variant	Exon 2 of 22	1		ENSP00000453306.1
ENSG00000259713	ENST00000559041.1	n.48-8613C>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72124 AN: 151954 Hom.: 18382 Cov.: 33

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.507 AC: 126547 AN: 249522 AF XY: 0.514

Gnomad AFR exome AF: 0.288

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.537

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.556 AC: 812058 AN: 1461824 Hom.: 230016 Cov.: 53 AF XY: 0.554 AC XY: 403207 AN XY: 727214

African (AFR) AF: 0.277 AC: 9288 AN: 33478

American (AMR) AF: 0.409 AC: 18301 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 14086 AN: 26136

East Asian (EAS) AF: 0.306 AC: 12140 AN: 39698

South Asian (SAS) AF: 0.482 AC: 41596 AN: 86254

European-Finnish (FIN) AF: 0.611 AC: 32618 AN: 53416

Middle Eastern (MID) AF: 0.443 AC: 2555 AN: 5768

European-Non Finnish (NFE) AF: 0.584 AC: 649928 AN: 1111962

Other (OTH) AF: 0.522 AC: 31546 AN: 60392

GnomAD4 genome AF: 0.474 AC: 72134 AN: 152072 Hom.: 18382 Cov.: 33 AF XY: 0.473 AC XY: 35200 AN XY: 74350

African (AFR) AF: 0.288 AC: 11951 AN: 41458

American (AMR) AF: 0.438 AC: 6693 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1843 AN: 3472

East Asian (EAS) AF: 0.326 AC: 1692 AN: 5184

South Asian (SAS) AF: 0.457 AC: 2203 AN: 4820

European-Finnish (FIN) AF: 0.615 AC: 6496 AN: 10558

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39585 AN: 67976

Other (OTH) AF: 0.478 AC: 1012 AN: 2116

Alfa AF: 0.536 Hom.: 76496

Bravo AF: 0.451

TwinsUK AF: 0.584 AC: 2166

ALSPAC AF: 0.580 AC: 2235

ESP6500AA AF: 0.294 AC: 1139

ESP6500EA AF: 0.567 AC: 4696

ExAC AF: 0.511 AC: 61822

Asia WGS AF: 0.388 AC: 1350 AN: 3478

EpiCase AF: 0.567

EpiControl AF: 0.564

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.3
DANN	Benign	0.82
DEOGEN2	Benign	0.0023	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0000090	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N;N
PhyloP100		0.44
PrimateAI	Benign	0.19	T
PROVEAN	Benign	3.8	N;N
REVEL	Benign	0.019
Sift	Benign	0.51	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.059
MPC		0.029
ClinPred		0.0015	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.34
Mutation Taster		=96/4	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: rs10775247; hg19: chr15-90126121; COSMIC: COSV51539303; COSMIC: COSV51539303;