chr15-89623926-T-A

Position:

chr15-89623926-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152259.4(TICRR):c.3616T>A(p.Phe1206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,612,814 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

TICRR
NM_152259.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.234

Variant links:

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]

TICRR links:

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]

KIF7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.056791782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICRR	NM_152259.4 linkuse as main transcript	c.3616T>A	p.Phe1206Ile	missense_variant	20/22	ENST00000268138.12	NP_689472.3	Q7Z2Z1-1
TICRR	NM_001308025.1 linkuse as main transcript	c.3613T>A	p.Phe1205Ile	missense_variant	20/22		NP_001294954.1	Q7Z2Z1-2
KIF7	XM_047432481.1 linkuse as main transcript	c.3847+4675A>T		intron_variant			XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TICRR	ENST00000268138.12 linkuse as main transcript	c.3616T>A	p.Phe1206Ile	missense_variant	20/22	5	NM_152259.4	ENSP00000268138.7	Q7Z2Z1-1
TICRR	ENST00000560985.5 linkuse as main transcript	c.3613T>A	p.Phe1205Ile	missense_variant	20/22	1		ENSP00000453306.1	Q7Z2Z1-2
KIF7	ENST00000558928.1 linkuse as main transcript	n.178+4675A>T		intron_variant		3		ENSP00000504283.1	A0A7I2V527

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

151012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000730

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000192

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000682

AC:

AN:

249436

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000142

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000252

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000106

AC:

AN:

151012

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73694

show subpopulations

Gnomad4 AFR

AF:

0.0000730

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000825

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2023

The c.3616T>A (p.F1206I) alteration is located in exon 20 (coding exon 20) of the TICRR gene. This alteration results from a T to A substitution at nucleotide position 3616, causing the phenylalanine (F) at amino acid position 1206 to be replaced by an isoleucine (I). 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

0.082

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.7

DANN

Benign

0.89

DEOGEN2

Benign

0.0071

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.28

T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.025

Sift

Uncertain

0.021

D;D

Sift4G

Benign

0.38

T;T

Polyphen

0.0040

B;.

Vest4

0.15

MutPred

0.10

Gain of glycosylation at T1201 (P = 0.1131);.;

MVP

0.040

MPC

0.043

ClinPred

0.028

GERP RS

-4.5

Varity_R

0.069

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over