1-47251517-A-G

Variant names:

• chr1-47251517-A-G
• rs2758735
• NM_001048166.1:c.3486T>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.3486T>C​(p.Pro1162Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,613,978 control chromosomes in the GnomAD database, including 207,731 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. P1162P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.43 (15910 hom., cov: 33)
  • Exomes 𝑓: 0.51 (191821 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.821

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 1-47251517-A-G is Benign according to our data. Variant chr1-47251517-A-G is described in ClinVar as [Benign]. Clinvar id is 94095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47251517-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.821 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIL	NM_001048166.1	c.3486T>C	p.Pro1162Pro	synonymous_variant	Exon 17 of 17	ENST00000371877.8	NP_001041631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIL	ENST00000371877.8	c.3486T>C	p.Pro1162Pro	synonymous_variant	Exon 17 of 17	1	NM_001048166.1	ENSP00000360944.3

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64739 AN: 152016 Hom.: 15893 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.502 AC: 126084 AN: 251182 Hom.: 33165 AF XY: 0.512 AC XY: 69517 AN XY: 135752

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.649

Gnomad EAS exome AF: 0.450

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.507 AC: 741146 AN: 1461842 Hom.: 191821 Cov.: 65 AF XY: 0.510 AC XY: 371022 AN XY: 727220

Gnomad4 AFR exome AF: 0.153

Gnomad4 AMR exome AF: 0.441

Gnomad4 ASJ exome AF: 0.644

Gnomad4 EAS exome AF: 0.418

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.512

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.426 AC: 64782 AN: 152136 Hom.: 15910 Cov.: 33 AF XY: 0.432 AC XY: 32106 AN XY: 74338

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.431

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.463

Alfa AF: 0.485 Hom.: 10099

Bravo AF: 0.396

Asia WGS AF: 0.492 AC: 1709 AN: 3478

EpiCase AF: 0.530

EpiControl AF: 0.526

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Microcephaly 7, primary, autosomal recessive Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.45

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: rs2758735; hg19: chr1-47717189;