rs142315727

Variant names:

• chr1-47251625-T-C
• rs142315727
• NM_001048166.1:c.3378A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-47251625-T-C
• chr1-47251625-T-G

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.3378A>G​(p.Arg1126Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,614,160 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (38 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.404
• Publications: 3 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=-0.55).
• BP6: Variant 1-47251625-T-C is Benign according to our data. Variant chr1-47251625-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.404 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00458 (698/152314) while in subpopulation NFE AF = 0.00779 (530/68028). AF 95% confidence interval is 0.00724. There are 2 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	NM_001048166.1	MANE Select	c.3378A>G	p.Arg1126Arg	synonymous	Exon 17 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.3375A>G	p.Arg1125Arg	synonymous	Exon 18 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.3375A>G	p.Arg1125Arg	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.3378A>G	p.Arg1126Arg	synonymous	Exon 17 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.3375A>G	p.Arg1125Arg	synonymous	Exon 18 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.3324A>G	p.Arg1108Arg	synonymous	Exon 17 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 698 AN: 152196 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00461 AC: 1159 AN: 251238 AF XY: 0.00460

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.00788

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00604 AC: 8829 AN: 1461846 Hom.: 38 Cov.: 33 AF XY: 0.00588 AC XY: 4277 AN XY: 727216

African (AFR) AF: 0.00111 AC: 37 AN: 33474

American (AMR) AF: 0.00188 AC: 84 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00106 AC: 91 AN: 86238

European-Finnish (FIN) AF: 0.00620 AC: 331 AN: 53414

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00717 AC: 7975 AN: 1112004

Other (OTH) AF: 0.00454 AC: 274 AN: 60394

GnomAD4 genome AF: 0.00458 AC: 698 AN: 152314 Hom.: 2 Cov.: 33 AF XY: 0.00443 AC XY: 330 AN XY: 74486

African (AFR) AF: 0.00144 AC: 60 AN: 41576

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00688 AC: 73 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00779 AC: 530 AN: 68028

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00567 Hom.: 1

Bravo AF: 0.00421

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Microcephaly 7, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.1
DANN	Benign	0.58
PhyloP100		0.40
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: rs142315727; hg19: chr1-47717297;