rs140448154

chr1-47280441-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001048166.1(STIL):c.2017A>G(p.Ser673Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,614,220 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.978

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028458238).
• BP6: Variant 1-47280441-T-C is Benign according to our data. Variant chr1-47280441-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 160053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47280441-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1620/152328) while in subpopulation AFR AF= 0.0371 (1541/41564). AF 95% confidence interval is 0.0355. There are 27 homozygotes in gnomad4. There are 744 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.2017A>G	p.Ser673Gly	missense_variant	12/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.2017A>G	p.Ser673Gly	missense_variant	12/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1616 AN: 152210 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00301 AC: 758 AN: 251460 Hom.: 6 AF XY: 0.00229 AC XY: 311 AN XY: 135910

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00123 AC: 1805 AN: 1461892 Hom.: 22 Cov.: 32 AF XY: 0.00108 AC XY: 782 AN XY: 727248

Gnomad4 AFR exome AF: 0.0403

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.0106 AC: 1620 AN: 152328 Hom.: 27 Cov.: 32 AF XY: 0.00999 AC XY: 744 AN XY: 74504

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00186 Hom.: 9

Bravo AF: 0.0127

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00385 AC: 467

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2015	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. -

Microcephaly 7, primary, autosomal recessive Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.025
Dann	Benign	0.57
DEOGEN2	Benign	0.14	T;.;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.53	T;T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.62	N;.;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.65	T;.;T;T;T
Sift4G	Benign	0.44	T;T;T;T;.
Polyphen		0.0	B;.;B;B;B
Vest4		0.073
MVP		0.22
MPC		0.093
ClinPred		0.000015	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.091

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140448154; hg19: chr1-47746113;