NM_000168.6:c.4609C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000168.6(GLI3):c.4609C>T(p.Arg1537Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,614,054 control chromosomes in the GnomAD database, including 2,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1537P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 106 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2117 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 10.0

Publications

21 publications found

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]

GLI3 Gene-Disease associations (from GenCC):

Greig cephalopolysyndactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
Pallister-Hall syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
polydactyly, postaxial, type A1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
polysyndactyly 4
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
tibial hemimelia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acrocallosal syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GLI3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007484019).

BP6

Variant 7-41964464-G-A is Benign according to our data. Variant chr7-41964464-G-A is described in ClinVar as Benign. ClinVar VariationId is 255443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.4609C>T	p.Arg1537Cys	missense_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3	P10071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8 link	c.4609C>T	p.Arg1537Cys	missense_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

AF:

0.0346

AC:

5265

AN:

152196

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0100

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0278

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0430

Gnomad FIN

AF:

0.0305

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0531

Gnomad OTH

AF:

0.0388

GnomAD2 exomes

AF:

0.0372

AC:

9353

AN:

251380

AF XY:

0.0395

show subpopulations

Gnomad AFR exome

AF:

0.00831

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0432

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0503

Gnomad OTH exome

AF:

0.0386

GnomAD4 exome

AF:

0.0510

AC:

74501

AN:

1461740

Hom.:

2117

Cov.:

AF XY:

0.0510

AC XY:

37119

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00798

AC:

267

AN:

33478

American (AMR)

AF:

0.0222

AC:

992

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0423

AC:

1105

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0459

AC:

3955

AN:

86256

European-Finnish (FIN)

AF:

0.0316

AC:

1690

AN:

53420

Middle Eastern (MID)

AF:

0.0394

AC:

227

AN:

5768

European-Non Finnish (NFE)

AF:

0.0570

AC:

63397

AN:

1111866

Other (OTH)

AF:

0.0473

AC:

2858

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

3972

7945

11917

15890

19862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2398

4796

7194

9592

11990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0345

AC:

5262

AN:

152314

Hom.:

106

Cov.:

AF XY:

0.0327

AC XY:

2432

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00998

AC:

415

AN:

41584

American (AMR)

AF:

0.0278

AC:

425

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.0427

AC:

206

AN:

4828

European-Finnish (FIN)

AF:

0.0305

AC:

324

AN:

10620

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0531

AC:

3611

AN:

68018

Other (OTH)

AF:

0.0384

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

262

523

785

1046

1308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0460

Hom.:

588

Bravo

AF:

0.0321

TwinsUK

AF:

0.0577

AC:

214

ALSPAC

AF:

0.0633

AC:

244

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0566

AC:

487

ExAC

AF:

0.0367

AC:

4452

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0554

EpiControl

AF:

0.0493

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31139930) -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Greig cephalopolysyndactyly syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pallister-Hall syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.0

D;.

REVEL

Benign

0.28

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.048

D;.

Polyphen

1.0

D;.

Vest4

0.24

MPC

1.2

ClinPred

0.031

GERP RS

6.0

Varity_R

0.37

gMVP

0.64

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over