chr15-89582933-G-A

Position:

• chr15-89582933-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152259.4(TICRR):​c.902G>A​(p.Arg301Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,613,536 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (73 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0570

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028099418).
• BP6: Variant 15-89582933-G-A is Benign according to our data. Variant chr15-89582933-G-A is described in ClinVar as [Benign]. Clinvar id is 782310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00245 (372/151972) while in subpopulation AMR AF= 0.0212 (323/15264). AF 95% confidence interval is 0.0193. There are 9 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.902G>A	p.Arg301Gln	missense_variant	2/22	ENST00000268138.12
TICRR	NM_001308025.1	c.902G>A	p.Arg301Gln	missense_variant	2/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.902G>A	p.Arg301Gln	missense_variant	2/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.902G>A	p.Arg301Gln	missense_variant	2/22	1		P4
	ENST00000559041.1	n.48-8570G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 372 AN: 151866 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00748 AC: 1864 AN: 249300 Hom.: 55 AF XY: 0.00547 AC XY: 740 AN XY: 135290

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00165 AC: 2406 AN: 1461564 Hom.: 73 Cov.: 37 AF XY: 0.00136 AC XY: 988 AN XY: 727036

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.0497

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00245 AC: 372 AN: 151972 Hom.: 9 Cov.: 33 AF XY: 0.00255 AC XY: 189 AN XY: 74262

Gnomad4 AFR AF: 0.000796

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.00515

ESP6500AA AF: 0.000528 AC: 2

ESP6500EA AF: 0.000729 AC: 6

ExAC AF: 0.00576 AC: 696

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.2
DANN	Benign	0.72
DEOGEN2	Benign	0.0023	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.014
Sift	Benign	0.25	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.20	B;.
Vest4		0.081
MVP		0.081
MPC		0.029
ClinPred		0.00075	T
GERP RS		-1.0
Varity_R		0.021
gMVP		0.26

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: rs150565858; hg19: chr15-90126164; COSMIC: COSV51547808; COSMIC: COSV51547808;