chr15-89623908-G-A

Position:

• chr15-89623908-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152259.4(TICRR):​c.3598G>A​(p.Gly1200Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,613,994 control chromosomes in the GnomAD database, including 149 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 0.017 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (77 hom.)
• Consequence: TICRR NM_152259.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.516

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023335218).
• BP6: Variant 15-89623908-G-A is Benign according to our data. Variant chr15-89623908-G-A is described in ClinVar as [Benign]. Clinvar id is 768724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICRR	NM_152259.4	c.3598G>A	p.Gly1200Ser	missense_variant	20/22	ENST00000268138.12	NP_689472.3
TICRR	NM_001308025.1	c.3595G>A	p.Gly1199Ser	missense_variant	20/22		NP_001294954.1
KIF7	XM_047432481.1	c.3847+4693C>T		intron_variant			XP_047288437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICRR	ENST00000268138.12	c.3598G>A	p.Gly1200Ser	missense_variant	20/22	5	NM_152259.4	ENSP00000268138.7
TICRR	ENST00000560985.5	c.3595G>A	p.Gly1199Ser	missense_variant	20/22	1		ENSP00000453306.1
KIF7	ENST00000558928.1	n.178+4693C>T		intron_variant		3		ENSP00000504283.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2603 AN: 152110 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00428 AC: 1067 AN: 249022 Hom.: 27 AF XY: 0.00341 AC XY: 461 AN XY: 135216

Gnomad AFR exome AF: 0.0608

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00184 AC: 2687 AN: 1461766 Hom.: 77 Cov.: 31 AF XY: 0.00160 AC XY: 1161 AN XY: 727172

Gnomad4 AFR exome AF: 0.0656

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.0171 AC: 2604 AN: 152228 Hom.: 72 Cov.: 32 AF XY: 0.0168 AC XY: 1248 AN XY: 74440

Gnomad4 AFR AF: 0.0589

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00300 Hom.: 27

Bravo AF: 0.0201

ESP6500AA AF: 0.0539 AC: 222

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00509 AC: 616

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.4
DANN	Benign	0.57
DEOGEN2	Benign	0.0026	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.84	N;N
REVEL	Benign	0.023
Sift	Benign	0.58	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.017	B;.
Vest4		0.044
MVP		0.040
MPC		0.025
ClinPred		0.0024	T
GERP RS		0.45
Varity_R		0.034
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80127545; hg19: chr15-90167139;