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rs147160336

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001048166.1(STIL):c.227C>T(p.Ser76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

STIL
NM_001048166.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.70
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.024368972).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STILNM_001048166.1 linkuse as main transcriptc.227C>T p.Ser76Leu missense_variant 4/17 ENST00000371877.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STILENST00000371877.8 linkuse as main transcriptc.227C>T p.Ser76Leu missense_variant 4/171 NM_001048166.1 P5Q15468-2

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152032
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000123
AC:
31
AN:
251440
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000246
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000235
AC:
343
AN:
1461788
Hom.:
0
Cov.:
32
AF XY:
0.000199
AC XY:
145
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000283
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152032
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000151
Hom.:
0
Bravo
AF:
0.000151
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000382
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly 7, primary, autosomal recessive Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 15, 2022This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 76 of the STIL protein (p.Ser76Leu). This variant is present in population databases (rs147160336, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STIL-related conditions. ClinVar contains an entry for this variant (Variation ID: 160055). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.52
Cadd
Benign
14
Dann
Benign
0.20
DEOGEN2
Benign
0.079
T;.;.;.;T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.82
T;T;T;T;T;T
M_CAP
Benign
0.0029
T
MetaRNN
Benign
0.024
T;T;T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-2.2
N;.;N;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
1.9
N;N;N;N;N;N
REVEL
Benign
0.073
Sift
Benign
0.85
T;T;T;T;T;T
Sift4G
Benign
0.76
T;T;T;T;.;.
Polyphen
0.0010
B;.;B;B;B;.
Vest4
0.16
MVP
0.20
MPC
0.091
ClinPred
0.015
T
GERP RS
3.1
Varity_R
0.021
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147160336; hg19: chr1-47767944; COSMIC: COSV54548935; COSMIC: COSV54548935; API