1-47281006-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001048166.1(STIL):c.1452C>G(p.Ser484=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,872 control chromosomes in the GnomAD database, including 13,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S484S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (3186 hom., cov: 32)
  • Exomes 𝑓: 0.098 (10113 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.184

Genes affected

STIL (HGNC:10879): (STIL centriolar assembly protein) This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-47281006-G-C is Benign according to our data. Variant chr1-47281006-G-C is described in ClinVar as [Benign]. Clinvar id is 160051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47281006-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.184 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.1452C>G	p.Ser484=	synonymous_variant	12/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.1452C>G	p.Ser484=	synonymous_variant	12/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24761 AN: 151954 Hom.: 3186 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0908

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0768

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.120 AC: 30058 AN: 251294 Hom.: 2911 AF XY: 0.118 AC XY: 16065 AN XY: 135818

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.0498

Gnomad ASJ exome AF: 0.0883

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0793

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0980 AC: 143303 AN: 1461800 Hom.: 10113 Cov.: 33 AF XY: 0.0998 AC XY: 72566 AN XY: 727190

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.0908

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.0552

Gnomad4 NFE exome AF: 0.0789

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.163 AC: 24784 AN: 152072 Hom.: 3186 Cov.: 32 AF XY: 0.163 AC XY: 12149 AN XY: 74310

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.0907

Gnomad4 ASJ AF: 0.0841

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.0530

Gnomad4 NFE AF: 0.0768

Gnomad4 OTH AF: 0.124

Alfa AF: 0.0688 Hom.: 170

Bravo AF: 0.175

Asia WGS AF: 0.222 AC: 773 AN: 3478

EpiCase AF: 0.0804

EpiControl AF: 0.0819

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Microcephaly 7, primary, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	5.5
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs10789505; hg19: chr1-47746678; COSMIC: COSV54548036;