GeneBe

rs846266

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000168.6(GLI3):ā€‹c.547A>Gā€‹(p.Thr183Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,607,848 control chromosomes in the GnomAD database, including 266,873 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.63 ( 31372 hom., cov: 23)
Exomes š‘“: 0.56 ( 235501 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.14
Variant links:
Genes affected
GLI3 (HGNC:4319): (GLI family zinc finger 3) This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.7114227E-7).
BP6
Variant 7-42048623-T-C is Benign according to our data. Variant chr7-42048623-T-C is described in ClinVar as [Benign]. Clinvar id is 255446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42048623-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLI3NM_000168.6 linkuse as main transcriptc.547A>G p.Thr183Ala missense_variant 5/15 ENST00000395925.8 NP_000159.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLI3ENST00000395925.8 linkuse as main transcriptc.547A>G p.Thr183Ala missense_variant 5/155 NM_000168.6 ENSP00000379258 P1

Frequencies

GnomAD3 genomes
AF:
0.633
AC:
93747
AN:
147998
Hom.:
31332
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.864
Gnomad AMI
AF:
0.566
Gnomad AMR
AF:
0.454
Gnomad ASJ
AF:
0.412
Gnomad EAS
AF:
0.568
Gnomad SAS
AF:
0.469
Gnomad FIN
AF:
0.589
Gnomad MID
AF:
0.420
Gnomad NFE
AF:
0.574
Gnomad OTH
AF:
0.565
GnomAD3 exomes
AF:
0.544
AC:
136825
AN:
251422
Hom.:
39173
AF XY:
0.543
AC XY:
73768
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.868
Gnomad AMR exome
AF:
0.353
Gnomad ASJ exome
AF:
0.430
Gnomad EAS exome
AF:
0.555
Gnomad SAS exome
AF:
0.479
Gnomad FIN exome
AF:
0.589
Gnomad NFE exome
AF:
0.574
Gnomad OTH exome
AF:
0.532
GnomAD4 exome
AF:
0.563
AC:
822062
AN:
1459732
Hom.:
235501
Cov.:
37
AF XY:
0.560
AC XY:
407017
AN XY:
726358
show subpopulations
Gnomad4 AFR exome
AF:
0.873
Gnomad4 AMR exome
AF:
0.368
Gnomad4 ASJ exome
AF:
0.425
Gnomad4 EAS exome
AF:
0.578
Gnomad4 SAS exome
AF:
0.476
Gnomad4 FIN exome
AF:
0.591
Gnomad4 NFE exome
AF:
0.571
Gnomad4 OTH exome
AF:
0.552
GnomAD4 genome
AF:
0.634
AC:
93840
AN:
148116
Hom.:
31372
Cov.:
23
AF XY:
0.626
AC XY:
45019
AN XY:
71922
show subpopulations
Gnomad4 AFR
AF:
0.865
Gnomad4 AMR
AF:
0.453
Gnomad4 ASJ
AF:
0.412
Gnomad4 EAS
AF:
0.568
Gnomad4 SAS
AF:
0.469
Gnomad4 FIN
AF:
0.589
Gnomad4 NFE
AF:
0.574
Gnomad4 OTH
AF:
0.562
Alfa
AF:
0.567
Hom.:
60989
Bravo
AF:
0.633
TwinsUK
AF:
0.578
AC:
2142
ALSPAC
AF:
0.560
AC:
2157
ESP6500AA
AF:
0.855
AC:
3767
ESP6500EA
AF:
0.563
AC:
4841
ExAC
AF:
0.563
AC:
68320
Asia WGS
AF:
0.518
AC:
1807
AN:
3476
EpiCase
AF:
0.559
EpiControl
AF:
0.551

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 16, 2016- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 20, 2020- -
Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Greig cephalopolysyndactyly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Polydactyly Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Pallister-Hall syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.050
BayesDel_addAF
Benign
-0.76
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
14
DANN
Benign
0.23
DEOGEN2
Benign
0.24
T;.
Eigen
Benign
-0.95
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.027
T;T
MetaRNN
Benign
5.7e-7
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.69
N;.
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.35
T
PROVEAN
Benign
2.1
N;.
REVEL
Benign
0.071
Sift
Benign
1.0
T;.
Sift4G
Benign
1.0
T;.
Polyphen
0.0
B;.
Vest4
0.026
MPC
0.13
ClinPred
0.0017
T
GERP RS
3.2
Varity_R
0.040
gMVP
0.30

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs846266; hg19: chr7-42088222; COSMIC: COSV67884691; COSMIC: COSV67884691; API