chr1-47260415-T-C

Variant names:

• chr1-47260415-T-C
• rs13376679
• NM_001048166.1:c.2954A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001048166.1(STIL):​c.2954A>G​(p.His985Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,613,810 control chromosomes in the GnomAD database, including 71,390 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5206 hom., cov: 32)
  • Exomes 𝑓: 0.29 (66184 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0110
• Publications: 32 publications found

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]

STIL Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• microcephaly 7, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00568372).
• BP6: Variant 1-47260415-T-C is Benign according to our data. Variant chr1-47260415-T-C is described in ClinVar as Benign. ClinVar VariationId is 94094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048166.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	NM_001048166.1	MANE Select	c.2954A>G	p.His985Arg	missense	Exon 16 of 17	NP_001041631.1
	STIL	NM_001282936.1		c.2951A>G	p.His984Arg	missense	Exon 17 of 18	NP_001269865.1
	STIL	NM_003035.2		c.2951A>G	p.His984Arg	missense	Exon 16 of 17	NP_003026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	ENST00000371877.8	TSL:1 MANE Select	c.2954A>G	p.His985Arg	missense	Exon 16 of 17	ENSP00000360944.3
	STIL	ENST00000360380.7	TSL:1	c.2951A>G	p.His984Arg	missense	Exon 17 of 18	ENSP00000353544.3
	STIL	ENST00000396221.6	TSL:1	c.2900A>G	p.His967Arg	missense	Exon 16 of 17	ENSP00000379523.2

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38426 AN: 152010 Hom.: 5203 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.239 AC: 59984 AN: 251460 AF XY: 0.246

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.0230

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.293 AC: 428455 AN: 1461682 Hom.: 66184 Cov.: 38 AF XY: 0.292 AC XY: 212198 AN XY: 727154

African (AFR) AF: 0.205 AC: 6873 AN: 33478

American (AMR) AF: 0.151 AC: 6774 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 6013 AN: 26134

East Asian (EAS) AF: 0.0172 AC: 681 AN: 39690

South Asian (SAS) AF: 0.234 AC: 20160 AN: 86250

European-Finnish (FIN) AF: 0.243 AC: 12962 AN: 53418

Middle Eastern (MID) AF: 0.318 AC: 1831 AN: 5766

European-Non Finnish (NFE) AF: 0.321 AC: 356532 AN: 1111836

Other (OTH) AF: 0.275 AC: 16629 AN: 60386

GnomAD4 genome AF: 0.253 AC: 38433 AN: 152128 Hom.: 5206 Cov.: 32 AF XY: 0.247 AC XY: 18371 AN XY: 74366

African (AFR) AF: 0.202 AC: 8357 AN: 41474

American (AMR) AF: 0.215 AC: 3284 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3472

East Asian (EAS) AF: 0.0254 AC: 132 AN: 5192

South Asian (SAS) AF: 0.209 AC: 1007 AN: 4818

European-Finnish (FIN) AF: 0.243 AC: 2575 AN: 10578

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21324 AN: 67980

Other (OTH) AF: 0.268 AC: 568 AN: 2116

Alfa AF: 0.286 Hom.: 23254

Bravo AF: 0.248

TwinsUK AF: 0.319 AC: 1183

ALSPAC AF: 0.321 AC: 1237

ESP6500AA AF: 0.219 AC: 966

ESP6500EA AF: 0.315 AC: 2710

ExAC AF: 0.242 AC: 29387

Asia WGS AF: 0.134 AC: 470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 24, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Mar 03, 2015

GeneDx

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

Apr 20, 2017

Athena Diagnostics

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

Microcephaly 7, primary, autosomal recessive Benign:2

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.2
DANN	Benign	0.47
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.011
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.030
Sift	Benign	0.31	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.043
MPC		0.13
ClinPred		0.0062	T
GERP RS		0.31
Varity_R		0.027
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13376679; hg19: chr1-47726087; COSMIC: COSV54551803; COSMIC: COSV54551803;