NM_001048166.1:c.3486T>C

Variant names:

• chr1-47251517-A-G
• rs2758735
• NM_001048166.1:c.3486T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001048166.1(STIL):​c.3486T>C​(p.Pro1162Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,613,978 control chromosomes in the GnomAD database, including 207,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1162P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.43 (15910 hom., cov: 33)
  • Exomes 𝑓: 0.51 (191821 hom.)
• Consequence: STIL NM_001048166.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.821
• Publications: 17 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=-0.85).
• BP6: Variant 1-47251517-A-G is Benign according to our data. Variant chr1-47251517-A-G is described in ClinVar as Benign. ClinVar VariationId is 94095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.821 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

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.3486T>C	p.Pro1162Pro	synonymous	Exon 17 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.3483T>C	p.Pro1161Pro	synonymous	Exon 18 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.3483T>C	p.Pro1161Pro	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.3486T>C	p.Pro1162Pro	synonymous	Exon 17 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.3483T>C	p.Pro1161Pro	synonymous	Exon 18 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.3432T>C	p.Pro1144Pro	synonymous	Exon 17 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64739 AN: 152016 Hom.: 15893 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.502 AC: 126084 AN: 251182 AF XY: 0.512

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.649

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.507 AC: 741146 AN: 1461842 Hom.: 191821 Cov.: 65 AF XY: 0.510 AC XY: 371022 AN XY: 727220

African (AFR) AF: 0.153 AC: 5130 AN: 33480

American (AMR) AF: 0.441 AC: 19724 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 16827 AN: 26132

East Asian (EAS) AF: 0.418 AC: 16606 AN: 39694

South Asian (SAS) AF: 0.537 AC: 46296 AN: 86252

European-Finnish (FIN) AF: 0.640 AC: 34159 AN: 53412

Middle Eastern (MID) AF: 0.526 AC: 3032 AN: 5768

European-Non Finnish (NFE) AF: 0.512 AC: 568952 AN: 1111984

Other (OTH) AF: 0.504 AC: 30420 AN: 60396

GnomAD4 genome AF: 0.426 AC: 64782 AN: 152136 Hom.: 15910 Cov.: 33 AF XY: 0.432 AC XY: 32106 AN XY: 74338

African (AFR) AF: 0.171 AC: 7105 AN: 41538

American (AMR) AF: 0.431 AC: 6583 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2277 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2314 AN: 5172

South Asian (SAS) AF: 0.551 AC: 2652 AN: 4814

European-Finnish (FIN) AF: 0.645 AC: 6810 AN: 10556

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35480 AN: 67986

Other (OTH) AF: 0.463 AC: 976 AN: 2108

Alfa AF: 0.485 Hom.: 10099

Bravo AF: 0.396

Asia WGS AF: 0.492 AC: 1709 AN: 3478

EpiCase AF: 0.530

EpiControl AF: 0.526

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Microcephaly 7, primary, autosomal recessive (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.45
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs2758735; hg19: chr1-47717189; COSMIC: COSV108067324;