rs149185431

Variant names:

• chr1-47282457-G-A
• rs149185431
• NM_001048166.1:c.1136C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001048166.1(STIL):​c.1136C>T​(p.Ser379Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,598,892 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S379S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (10 hom.)
• Consequence: STIL NM_001048166.1 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5 O:1
• Conservation: PhyloP100: 3.28
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066698194).
• BP6: Variant 1-47282457-G-A is Benign according to our data. Variant chr1-47282457-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 160049.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00245 (373/152268) while in subpopulation NFE AF = 0.00397 (270/67998). AF 95% confidence interval is 0.00358. There are 0 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.1136C>T	p.Ser379Phe	missense splice_region	Exon 11 of 17	NP_001041631.1	Q15468-2
	STIL	NM_001282936.1		c.1136C>T	p.Ser379Phe	missense splice_region	Exon 12 of 18	NP_001269865.1	Q15468-1
	STIL	NM_003035.2		c.1136C>T	p.Ser379Phe	missense splice_region	Exon 11 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.1136C>T	p.Ser379Phe	missense splice_region	Exon 11 of 17	ENSP00000360944.3	Q15468-2
	STIL	ENST00000360380.7	TSL:1	c.1136C>T	p.Ser379Phe	missense splice_region	Exon 12 of 18	ENSP00000353544.3	Q15468-1
	STIL	ENST00000396221.6	TSL:1	c.1136C>T	p.Ser379Phe	missense splice_region	Exon 11 of 17	ENSP00000379523.2	E9PSF2

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00225 AC: 562 AN: 250054 AF XY: 0.00219

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000440

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00344 AC: 4974 AN: 1446624 Hom.: 10 Cov.: 27 AF XY: 0.00332 AC XY: 2396 AN XY: 720704

African (AFR) AF: 0.000754 AC: 25 AN: 33178

American (AMR) AF: 0.00199 AC: 89 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000768 AC: 20 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.000640 AC: 55 AN: 85936

European-Finnish (FIN) AF: 0.000557 AC: 29 AN: 52080

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5738

European-Non Finnish (NFE) AF: 0.00417 AC: 4583 AN: 1099476

Other (OTH) AF: 0.00284 AC: 170 AN: 59916

GnomAD4 genome AF: 0.00245 AC: 373 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74452

African (AFR) AF: 0.000842 AC: 35 AN: 41568

American (AMR) AF: 0.00392 AC: 60 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00397 AC: 270 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00311 Hom.: 0

Bravo AF: 0.00246

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00240 AC: 291

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.3
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.034
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.029	B
Vest4		0.22
MVP		0.48
MPC		0.12
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.14
Mutation Taster		=92/8	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: rs149185431; hg19: chr1-47748129; COSMIC: COSV54550229;