rs146387723

Variant names:

• chr1-47251217-C-T
• rs146387723
• NM_001048166.1:c.3786G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001048166.1(STIL):​c.3786G>A​(p.Thr1262Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00707 in 1,612,162 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (74 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.132
• Publications: 4 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-47251217-C-T is Benign according to our data. Variant chr1-47251217-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.132 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00512 (779/152294) while in subpopulation SAS AF = 0.019 (92/4830). AF 95% confidence interval is 0.0159. There are 3 homozygotes in GnomAd4. There are 405 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	NM_001048166.1	MANE Select	c.3786G>A	p.Thr1262Thr	synonymous	Exon 17 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.3783G>A	p.Thr1261Thr	synonymous	Exon 18 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.3783G>A	p.Thr1261Thr	synonymous	Exon 17 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.3786G>A	p.Thr1262Thr	synonymous	Exon 17 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.3783G>A	p.Thr1261Thr	synonymous	Exon 18 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.3732G>A	p.Thr1244Thr	synonymous	Exon 17 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152176 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00742 AC: 1855 AN: 250004 AF XY: 0.00867

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00502

Gnomad ASJ exome AF: 0.00880

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.00727 AC: 10620 AN: 1459868 Hom.: 74 Cov.: 30 AF XY: 0.00783 AC XY: 5686 AN XY: 726054

African (AFR) AF: 0.00114 AC: 38 AN: 33292

American (AMR) AF: 0.00534 AC: 237 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00794 AC: 207 AN: 26072

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0224 AC: 1926 AN: 85792

European-Finnish (FIN) AF: 0.00348 AC: 186 AN: 53398

Middle Eastern (MID) AF: 0.0162 AC: 93 AN: 5754

European-Non Finnish (NFE) AF: 0.00675 AC: 7498 AN: 1111208

Other (OTH) AF: 0.00720 AC: 434 AN: 60294

GnomAD4 genome AF: 0.00512 AC: 779 AN: 152294 Hom.: 3 Cov.: 33 AF XY: 0.00544 AC XY: 405 AN XY: 74488

African (AFR) AF: 0.00135 AC: 56 AN: 41556

American (AMR) AF: 0.00484 AC: 74 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4830

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00709 AC: 482 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00632 Hom.: 1

Bravo AF: 0.00516

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00747

EpiControl AF: 0.00664

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Microcephaly 7, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.4
DANN	Benign	0.54
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs146387723; hg19: chr1-47716889; COSMIC: COSV54548848;