Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001048166.1(STIL):c.1055G>A(p.Arg352His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,613,536 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 2 hom. )

Consequence

STIL
NM_001048166.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.157

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
microcephaly 7, primary, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

STIL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007013947).

BP6

Variant 1-47287629-C-T is Benign according to our data. Variant chr1-47287629-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235445.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00304 (463/152230) while in subpopulation AFR AF = 0.00989 (411/41542). AF 95% confidence interval is 0.0091. There are 2 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048166.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STIL	NM_001048166.1	MANE Select	c.1055G>A	p.Arg352His	missense	Exon 10 of 17	NP_001041631.1
STIL	NM_001282936.1		c.1055G>A	p.Arg352His	missense	Exon 11 of 18	NP_001269865.1
STIL	NM_003035.2		c.1055G>A	p.Arg352His	missense	Exon 10 of 17	NP_003026.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STIL	ENST00000371877.8	TSL:1 MANE Select	c.1055G>A	p.Arg352His	missense	Exon 10 of 17	ENSP00000360944.3
STIL	ENST00000360380.7	TSL:1	c.1055G>A	p.Arg352His	missense	Exon 11 of 18	ENSP00000353544.3
STIL	ENST00000396221.6	TSL:1	c.1055G>A	p.Arg352His	missense	Exon 10 of 17	ENSP00000379523.2

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

463

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00992

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.000832

AC:

209

AN:

251274

AF XY:

0.000626

show subpopulations

Gnomad AFR exome

AF:

0.00949

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000595

AC:

869

AN:

1461306

Hom.:

Cov.:

AF XY:

0.000547

AC XY:

398

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.0106

AC:

355

AN:

33456

American (AMR)

AF:

0.000291

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000397

AC:

441

AN:

1111702

Other (OTH)

AF:

0.000828

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00304

AC:

463

AN:

152230

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

226

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00989

AC:

411

AN:

41542

American (AMR)

AF:

0.000916

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68010

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00331

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000980

AC:

119

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000328

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Microcephaly 7, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.5

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.080

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

PhyloP100

-0.16

PrimateAI

Benign

0.17

PROVEAN

Benign

0.66

REVEL

Benign

0.022

Sift

Benign

0.65

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.10

MVP

0.38

MPC

0.13

ClinPred

0.0018

GERP RS

0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.018

gMVP

0.088

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs141678367

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over