chr15-89575770-G-C

Position:

• chr15-89575770-G-C

Variant summary

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

The NM_152259.4(TICRR):​c.184G>C​(p.Val62Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

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 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=0.2224086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICRR	NM_152259.4	c.184G>C	p.Val62Leu	missense_variant	1/22	ENST00000268138.12
TICRR	NM_001308025.1	c.184G>C	p.Val62Leu	missense_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICRR	ENST00000268138.12	c.184G>C	p.Val62Leu	missense_variant	1/22	5	NM_152259.4	A2
TICRR	ENST00000560985.5	c.184G>C	p.Val62Leu	missense_variant	1/22	1		P4
	ENST00000559041.1	n.48-15733G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456910 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 23, 2024

The c.184G>C (p.V62L) alteration is located in exon 1 (coding exon 1) of the TICRR gene. This alteration results from a G to C substitution at nucleotide position 184, causing the valine (V) at amino acid position 62 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.92	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.085
Sift	Benign	0.48	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.89	P;.
Vest4		0.21
MutPred		0.12		Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);
MVP		0.29
MPC		1.7
ClinPred		0.95	D
GERP RS		4.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.14
gMVP		0.41

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: rs374157354; hg19: chr15-90119001;