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GeneBe

rs2228225

chr12-57465648-G-Achr12-57465648-G-Cchr12-57465648-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005269.3(GLI1):c.576G>A(p.Glu192=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,246 control chromosomes in the GnomAD database, including 278,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 19404 hom., cov: 32)
Exomes 𝑓: 0.59 ( 258808 hom. )

Consequence

GLI1
NM_005269.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.94
Variant links:
Genes affected
GLI1 (HGNC:4317): (GLI family zinc finger 1) This gene encodes a member of the Kruppel family of zinc finger proteins. The encoded transcription factor is activated by the sonic hedgehog signal transduction cascade and regulates stem cell proliferation. The activity and nuclear localization of this protein is negatively regulated by p53 in an inhibitory loop. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-57465648-G-A is Benign according to our data. Variant chr12-57465648-G-A is described in ClinVar as [Benign]. Clinvar id is 1277191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.94 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLI1NM_005269.3 linkuse as main transcriptc.576G>A p.Glu192= synonymous_variant 6/12 ENST00000228682.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLI1ENST00000228682.7 linkuse as main transcriptc.576G>A p.Glu192= synonymous_variant 6/121 NM_005269.3 P1P08151-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.475
AC:
72248
AN:
151976
Hom.:
19409
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.238
Gnomad AMI
AF:
0.488
Gnomad AMR
AF:
0.435
Gnomad ASJ
AF:
0.580
Gnomad EAS
AF:
0.323
Gnomad SAS
AF:
0.427
Gnomad FIN
AF:
0.516
Gnomad MID
AF:
0.677
Gnomad NFE
AF:
0.630
Gnomad OTH
AF:
0.524
GnomAD3 exomes
AF:
0.496
AC:
124507
AN:
251084
Hom.:
33772
AF XY:
0.510
AC XY:
69158
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.222
Gnomad AMR exome
AF:
0.321
Gnomad ASJ exome
AF:
0.581
Gnomad EAS exome
AF:
0.292
Gnomad SAS exome
AF:
0.429
Gnomad FIN exome
AF:
0.510
Gnomad NFE exome
AF:
0.626
Gnomad OTH exome
AF:
0.560
GnomAD4 exome
AF:
0.586
AC:
856022
AN:
1461152
Hom.:
258808
Cov.:
46
AF XY:
0.584
AC XY:
424434
AN XY:
726892
show subpopulations
Gnomad4 AFR exome
AF:
0.225
Gnomad4 AMR exome
AF:
0.336
Gnomad4 ASJ exome
AF:
0.579
Gnomad4 EAS exome
AF:
0.400
Gnomad4 SAS exome
AF:
0.432
Gnomad4 FIN exome
AF:
0.515
Gnomad4 NFE exome
AF:
0.631
Gnomad4 OTH exome
AF:
0.549
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.475
AC:
72253
AN:
152094
Hom.:
19404
Cov.:
32
AF XY:
0.468
AC XY:
34785
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.238
Gnomad4 AMR
AF:
0.435
Gnomad4 ASJ
AF:
0.580
Gnomad4 EAS
AF:
0.323
Gnomad4 SAS
AF:
0.427
Gnomad4 FIN
AF:
0.516
Gnomad4 NFE
AF:
0.630
Gnomad4 OTH
AF:
0.519
Alfa
AF:
0.590
Hom.:
46537
Bravo
AF:
0.454
Asia WGS
AF:
0.359
AC:
1252
AN:
3478
EpiCase
AF:
0.639
EpiControl
AF:
0.641

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Polydactyly, postaxial, type A8 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
GLI1-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 30, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxFeb 21, 2019- -
Preaxial hand polydactyly Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
Cadd
Benign
5.2
Dann
Benign
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2228225; hg19: chr12-57859431; COSMIC: COSV57357787; COSMIC: COSV57357787; API