1-47251625-T-C

Position:

• chr1-47251625-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001048166.1(STIL):​c.3378A>G​(p.Arg1126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,614,160 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (38 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.404

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-47251625-T-C is Benign according to our data. Variant chr1-47251625-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 160063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47251625-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.404 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.3378A>G	p.Arg1126=	synonymous_variant	17/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.3378A>G	p.Arg1126=	synonymous_variant	17/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 698 AN: 152196 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00461 AC: 1159 AN: 251238 Hom.: 3 AF XY: 0.00460 AC XY: 624 AN XY: 135786

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.00788

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00604 AC: 8829 AN: 1461846 Hom.: 38 Cov.: 33 AF XY: 0.00588 AC XY: 4277 AN XY: 727216

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.00620

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00458 AC: 698 AN: 152314 Hom.: 2 Cov.: 33 AF XY: 0.00443 AC XY: 330 AN XY: 74486

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00688

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00582 Hom.: 1

Bravo AF: 0.00421

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	STIL: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2019	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2014	- -

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	-0.55
CADD	Benign	7.1
DANN	Benign	0.58

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: rs142315727; hg19: chr1-47717297;