rs149185431

Positions:

chr1-47282457-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000371877.8(STIL):c.1136C>T(p.Ser379Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,598,892 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S379S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 10 hom. )

Consequence

STIL
ENST00000371877.8 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5O:1

Conservation

PhyloP100: 3.28

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]

STIL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066698194).

BP6

Variant 1-47282457-G-A is Benign according to our data. Variant chr1-47282457-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160049.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3, Likely_benign=4, not_provided=1}. Variant chr1-47282457-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STIL	NM_001048166.1 linkuse as main transcript	c.1136C>T	p.Ser379Phe	missense_variant, splice_region_variant	11/17	ENST00000371877.8	NP_001041631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STIL	ENST00000371877.8 linkuse as main transcript	c.1136C>T	p.Ser379Phe	missense_variant, splice_region_variant	11/17	1	NM_001048166.1	ENSP00000360944	P5	Q15468-2

Frequencies

GnomAD3 genomes

AF:

0.00245

AC:

373

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00397

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00225

AC:

562

AN:

250054

Hom.:

AF XY:

0.00219

AC XY:

296

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.000440

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00344

AC:

4974

AN:

1446624

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

2396

AN XY:

720704

show subpopulations

Gnomad4 AFR exome

AF:

0.000754

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000640

Gnomad4 FIN exome

AF:

0.000557

Gnomad4 NFE exome

AF:

0.00417

Gnomad4 OTH exome

AF:

0.00284

GnomAD4 genome

AF:

0.00245

AC:

373

AN:

152268

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00397

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00317

Hom.:

Bravo

AF:

0.00246

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00240

AC:

291

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly 7, primary, autosomal recessive

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Uncertain significance and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 28, 2012	- -
Uncertain significance, 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). 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

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	STIL: BP4, BP5 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2021	This variant is associated with the following publications: (PMID: 26548919, 23772360) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.36

T;.;.;.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.030

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.0067

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.;M;.;.

MutationTaster

Benign

0.77

N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.0

D;.;D;D;D

REVEL

Benign

0.034

Sift

Benign

0.15

T;.;T;T;T

Sift4G

Benign

0.30

T;T;T;T;.

Polyphen

0.029

B;.;B;B;B

Vest4

0.22

MVP

0.48

MPC

0.12

ClinPred

0.021

GERP RS

3.9

Varity_R

0.12

gMVP

0.14

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over