1-47280441-T-C

Variant names:

• chr1-47280441-T-C
• rs140448154
• NM_001048166.1:c.2017A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001048166.1(STIL):​c.2017A>G​(p.Ser673Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,614,220 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.978
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028458238).
• BP6: Variant 1-47280441-T-C is Benign according to our data. Variant chr1-47280441-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1620/152328) while in subpopulation AFR AF = 0.0371 (1541/41564). AF 95% confidence interval is 0.0355. There are 27 homozygotes in GnomAd4. There are 744 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.2017A>G	p.Ser673Gly	missense	Exon 12 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.2017A>G	p.Ser673Gly	missense	Exon 13 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.2017A>G	p.Ser673Gly	missense	Exon 12 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.2017A>G	p.Ser673Gly	missense	Exon 12 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.2017A>G	p.Ser673Gly	missense	Exon 13 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.2017A>G	p.Ser673Gly	missense	Exon 12 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1616 AN: 152210 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00301 AC: 758 AN: 251460 AF XY: 0.00229

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00123 AC: 1805 AN: 1461892 Hom.: 22 Cov.: 32 AF XY: 0.00108 AC XY: 782 AN XY: 727248

African (AFR) AF: 0.0403 AC: 1349 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1112010

Other (OTH) AF: 0.00258 AC: 156 AN: 60396

GnomAD4 genome AF: 0.0106 AC: 1620 AN: 152328 Hom.: 27 Cov.: 32 AF XY: 0.00999 AC XY: 744 AN XY: 74504

African (AFR) AF: 0.0371 AC: 1541 AN: 41564

American (AMR) AF: 0.00327 AC: 50 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00422 Hom.: 21

Bravo AF: 0.0127

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00385 AC: 467

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Microcephaly 7, primary, autosomal recessive (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.025
DANN	Benign	0.57
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N
PhyloP100		-0.98
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.012
Sift	Benign	0.65	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.073
MVP		0.22
MPC		0.093
ClinPred		0.000015	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.091
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140448154; hg19: chr1-47746113; COSMIC: COSV107290898;