rs369348360

chr1-47282367-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001048166.1(STIL):c.1226G>C(p.Ser409Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S409S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.15

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-47282367-C-G is Pathogenic according to our data. Variant chr1-47282367-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402198.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-47282367-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21301207).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.1226G>C	p.Ser409Thr	missense_variant	11/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.1226G>C	p.Ser409Thr	missense_variant	11/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250784 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1459858 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.8	M;.;M;.;.
MutationTaster	Benign	0.91	D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;.;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.077	T;.;T;T;T
Sift4G	Uncertain	0.043	D;D;D;D;.
Polyphen		0.99	D;.;D;D;D
Vest4		0.52
MVP		0.68
MPC		0.44
ClinPred		0.90	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs369348360; hg19: chr1-47748039;