1-47301645-C-A

Variant names:

• chr1-47301645-C-A
• rs1553181461
• NM_001048166.1:c.369G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001048166.1(STIL):​c.369G>T​(p.Leu123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.696
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30516237).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	NM_001048166.1	MANE Select	c.369G>T	p.Leu123Phe	missense	Exon 5 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.369G>T	p.Leu123Phe	missense	Exon 6 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.369G>T	p.Leu123Phe	missense	Exon 5 of 17	NP_003026.2	Q15468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	ENST00000371877.8	TSL:1 MANE Select	c.369G>T	p.Leu123Phe	missense	Exon 5 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.369G>T	p.Leu123Phe	missense	Exon 6 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.369G>T	p.Leu123Phe	missense	Exon 5 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461742 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.70
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.23
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		0.94	P
Vest4		0.29
MutPred		0.32		Loss of ubiquitination at K127 (P = 0.0907)
MVP		0.62
MPC		0.19
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.42
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1553181461; hg19: chr1-47767317;