1-47302242-G-A

Variant names:

• chr1-47302242-G-A
• rs3125630
• NM_001048166.1:c.257C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001048166.1(STIL):​c.257C>T​(p.Ala86Val) variant causes a missense change. The variant allele was found at a frequency of 0.501 in 1,606,720 control chromosomes in the GnomAD database, including 208,945 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27290 hom., cov: 32)
  • Exomes 𝑓: 0.49 (181655 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 5.35
• Publications: 47 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=5.9604446E-7).
• BP6: Variant 1-47302242-G-A is Benign according to our data. Variant chr1-47302242-G-A is described in ClinVar as Benign. ClinVar VariationId is 21354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 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.257C>T	p.Ala86Val	missense	Exon 4 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.257C>T	p.Ala86Val	missense	Exon 5 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.257C>T	p.Ala86Val	missense	Exon 4 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.257C>T	p.Ala86Val	missense	Exon 4 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.257C>T	p.Ala86Val	missense	Exon 5 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.257C>T	p.Ala86Val	missense	Exon 4 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87330 AN: 151862 Hom.: 27255 Cov.: 32

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.498 AC: 125160 AN: 251140 AF XY: 0.488

Gnomad AFR exome AF: 0.841

Gnomad AMR exome AF: 0.555

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.494 AC: 718056 AN: 1454740 Hom.: 181655 Cov.: 32 AF XY: 0.490 AC XY: 355055 AN XY: 724056

African (AFR) AF: 0.849 AC: 28288 AN: 33328

American (AMR) AF: 0.557 AC: 24889 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9259 AN: 26086

East Asian (EAS) AF: 0.581 AC: 23053 AN: 39650

South Asian (SAS) AF: 0.464 AC: 39931 AN: 86088

European-Finnish (FIN) AF: 0.362 AC: 19312 AN: 53370

Middle Eastern (MID) AF: 0.473 AC: 2719 AN: 5746

European-Non Finnish (NFE) AF: 0.489 AC: 540725 AN: 1105616

Other (OTH) AF: 0.497 AC: 29880 AN: 60146

GnomAD4 genome AF: 0.575 AC: 87411 AN: 151980 Hom.: 27290 Cov.: 32 AF XY: 0.569 AC XY: 42257 AN XY: 74262

African (AFR) AF: 0.831 AC: 34487 AN: 41480

American (AMR) AF: 0.569 AC: 8676 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3468

East Asian (EAS) AF: 0.553 AC: 2854 AN: 5164

South Asian (SAS) AF: 0.449 AC: 2159 AN: 4812

European-Finnish (FIN) AF: 0.355 AC: 3750 AN: 10550

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32556 AN: 67956

Other (OTH) AF: 0.536 AC: 1128 AN: 2104

Alfa AF: 0.511 Hom.: 71373

Bravo AF: 0.605

TwinsUK AF: 0.488 AC: 1809

ALSPAC AF: 0.492 AC: 1895

ESP6500AA AF: 0.820 AC: 3612

ESP6500EA AF: 0.477 AC: 4102

ExAC AF: 0.502 AC: 60992

Asia WGS AF: 0.508 AC: 1770 AN: 3478

EpiCase AF: 0.471

EpiControl AF: 0.474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephaly 7, primary, autosomal recessive (5)
-	-	4	not provided (4)
-	-	4	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.25
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.078	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.9	N
PhyloP100		5.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.10
ClinPred		0.011	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.23
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: rs3125630; hg19: chr1-47767914; COSMIC: COSV54548838; COSMIC: COSV54548838;