rs28472545

chr1-47281196-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001048166.1(STIL):c.1262A>C(p.Gln421Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q421H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.85

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17405829).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.1262A>C	p.Gln421Pro	missense_variant	12/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.1262A>C	p.Gln421Pro	missense_variant	12/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Microcephaly 7, primary, autosomal recessive Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;.;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;T;D;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;.;M;.;.
MutationTaster	Benign	0.77	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.4	N;.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.11	T;.;T;T;T
Sift4G	Benign	0.22	T;T;T;T;.
Polyphen		1.0	D;.;D;D;D
Vest4		0.39
MutPred		0.29		Gain of catalytic residue at Q421 (P = 0.0046);.;Gain of catalytic residue at Q421 (P = 0.0046);Gain of catalytic residue at Q421 (P = 0.0046);.;
MVP		0.75
MPC		0.52
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.18
gMVP		0.34

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: rs28472545; hg19: chr1-47746868;