rs146387723

chr1-47251217-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001048166.1(STIL):c.3786G>A(p.Thr1262=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00707 in 1,612,162 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (74 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.132

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=-0.66).
• BP6: Variant 1-47251217-C-T is Benign according to our data. Variant chr1-47251217-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47251217-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00512 (779/152294) while in subpopulation SAS AF= 0.019 (92/4830). AF 95% confidence interval is 0.0159. There are 3 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.3786G>A	p.Thr1262=	synonymous_variant	17/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.3786G>A	p.Thr1262=	synonymous_variant	17/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152176 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00742 AC: 1855 AN: 250004 Hom.: 17 AF XY: 0.00867 AC XY: 1171 AN XY: 135064

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00502

Gnomad ASJ exome AF: 0.00880

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.00727 AC: 10620 AN: 1459868 Hom.: 74 Cov.: 30 AF XY: 0.00783 AC XY: 5686 AN XY: 726054

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00534

Gnomad4 ASJ exome AF: 0.00794

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.00675

Gnomad4 OTH exome AF: 0.00720

GnomAD4 genome AF: 0.00512 AC: 779 AN: 152294 Hom.: 3 Cov.: 33 AF XY: 0.00544 AC XY: 405 AN XY: 74488

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00709

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00632 Hom.: 1

Bravo AF: 0.00516

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -

Microcephaly 7, primary, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	5.4
Dann	Benign	0.54
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: rs146387723; hg19: chr1-47716889; COSMIC: COSV54548848;