chr1-47251573-C-T

Variant names:

• chr1-47251573-C-T
• rs112563569
• NM_001048166.1:c.3430G>A

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.3430G>A​(p.Asp1144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,806 control chromosomes in the GnomAD database, including 24 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (13 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.577
• Publications: 5 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: ClinGen, Orphanet
• microcephaly 7, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=0.0019308627).
• BP6: Variant 1-47251573-C-T is Benign according to our data. Variant chr1-47251573-C-T is described in ClinVar as Benign. ClinVar VariationId is 160065.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 = 0.00672 (1023/152268) while in subpopulation AFR AF = 0.0226 (938/41554). AF 95% confidence interval is 0.0214. There are 11 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.3430G>A	p.Asp1144Asn	missense	Exon 17 of 17	NP_001041631.1
	STIL	NM_001282936.1		c.3427G>A	p.Asp1143Asn	missense	Exon 18 of 18	NP_001269865.1
	STIL	NM_003035.2		c.3427G>A	p.Asp1143Asn	missense	Exon 17 of 17	NP_003026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STIL	ENST00000371877.8	TSL:1 MANE Select	c.3430G>A	p.Asp1144Asn	missense	Exon 17 of 17	ENSP00000360944.3
	STIL	ENST00000360380.7	TSL:1	c.3427G>A	p.Asp1143Asn	missense	Exon 18 of 18	ENSP00000353544.3
	STIL	ENST00000396221.6	TSL:1	c.3376G>A	p.Asp1126Asn	missense	Exon 17 of 17	ENSP00000379523.2

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1016 AN: 152150 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00177 AC: 445 AN: 251036 AF XY: 0.00136

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000844 AC: 1233 AN: 1461538 Hom.: 13 Cov.: 33 AF XY: 0.000754 AC XY: 548 AN XY: 727050

African (AFR) AF: 0.0230 AC: 770 AN: 33430

American (AMR) AF: 0.00150 AC: 67 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86230

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53410

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000213 AC: 237 AN: 1111824

Other (OTH) AF: 0.00215 AC: 130 AN: 60384

GnomAD4 genome AF: 0.00672 AC: 1023 AN: 152268 Hom.: 11 Cov.: 33 AF XY: 0.00655 AC XY: 488 AN XY: 74456

African (AFR) AF: 0.0226 AC: 938 AN: 41554

American (AMR) AF: 0.00327 AC: 50 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00229 Hom.: 7

Bravo AF: 0.00728

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00208 AC: 253

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.46
DANN	Benign	0.41
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.58
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.015
Sift	Benign	0.93	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.15
MPC		0.10
ClinPred		0.00060	T
GERP RS		-0.68
Varity_R		0.022
gMVP		0.087
Mutation Taster		=98/2	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: rs112563569; hg19: chr1-47717245;