dbSNP rs28472545: STIL:p.Gln421Pro (chr1-47281196-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.85

Publications

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

STIL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17405829).

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	UniProt
STIL	NM_001048166.1	MANE Select	c.1262A>C	p.Gln421Pro	missense	Exon 12 of 17	NP_001041631.1	Q15468-2
STIL	NM_001282936.1		c.1262A>C	p.Gln421Pro	missense	Exon 13 of 18	NP_001269865.1	Q15468-1
STIL	NM_003035.2		c.1262A>C	p.Gln421Pro	missense	Exon 12 of 17	NP_003026.2	Q15468-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STIL	ENST00000371877.8	TSL:1 MANE Select	c.1262A>C	p.Gln421Pro	missense	Exon 12 of 17	ENSP00000360944.3	Q15468-2
STIL	ENST00000360380.7	TSL:1	c.1262A>C	p.Gln421Pro	missense	Exon 13 of 18	ENSP00000353544.3	Q15468-1
STIL	ENST00000396221.6	TSL:1	c.1262A>C	p.Gln421Pro	missense	Exon 12 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly 7, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

M_CAP

Benign

0.022

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.6

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.4

REVEL

Benign

0.11

Sift

Benign

0.11

Sift4G

Benign

0.22

Polyphen

1.0

Vest4

0.39

MutPred

0.29

Gain of catalytic residue at Q421 (P = 0.0046)

MVP

0.75

MPC

0.52

ClinPred

0.96

GERP RS

4.5

Varity_R

0.18

gMVP

0.34

Mutation Taster

=88/12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over