chr7-41966080-G-A

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.2993C>T(p.Pro998Leu) variant causes a missense change. The variant allele was found at a frequency of 0.346 in 1,567,904 control chromosomes in the GnomAD database, including 102,269 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. P998A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 9226 hom., cov: 32)

Exomes 𝑓: 0.35 ( 93043 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.99

Publications

45 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=1.0673986E-6).

BP6

Variant 7-41966080-G-A is Benign according to our data. Variant chr7-41966080-G-A is described in ClinVar as Benign. ClinVar VariationId is 255433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.2993C>T	p.Pro998Leu	missense_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8 link	c.2993C>T	p.Pro998Leu	missense_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49128

AN:

151778

Hom.:

9209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.189

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.439

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.425

AC:

74159

AN:

174410

AF XY:

0.420

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.569

Gnomad ASJ exome

AF:

0.394

Gnomad EAS exome

AF:

0.788

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.388

GnomAD4 exome

AF:

0.348

AC:

493056

AN:

1416008

Hom.:

93043

Cov.:

AF XY:

0.351

AC XY:

246594

AN XY:

701882

show subpopulations

African (AFR)

AF:

0.189

AC:

6165

AN:

32616

American (AMR)

AF:

0.551

AC:

22203

AN:

40312

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

10023

AN:

25340

East Asian (EAS)

AF:

0.819

AC:

30855

AN:

37696

South Asian (SAS)

AF:

0.465

AC:

38482

AN:

82838

European-Finnish (FIN)

AF:

0.326

AC:

12281

AN:

37716

Middle Eastern (MID)

AF:

0.362

AC:

1984

AN:

5488

European-Non Finnish (NFE)

AF:

0.319

AC:

349665

AN:

1095124

Other (OTH)

AF:

0.363

AC:

21398

AN:

58878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

19291

38582

57873

77164

96455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11718

23436

35154

46872

58590

<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:

0.324

AC:

49176

AN:

151896

Hom.:

9226

Cov.:

AF XY:

0.331

AC XY:

24603

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.189

AC:

7837

AN:

41500

American (AMR)

AF:

0.440

AC:

6723

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.409

AC:

1419

AN:

3470

East Asian (EAS)

AF:

0.805

AC:

4072

AN:

5060

South Asian (SAS)

AF:

0.492

AC:

2371

AN:

4816

European-Finnish (FIN)

AF:

0.336

AC:

3549

AN:

10572

Middle Eastern (MID)

AF:

0.315

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.324

AC:

21995

AN:

67880

Other (OTH)

AF:

0.347

AC:

734

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1601

3202

4803

6404

8005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.329

Hom.:

5735

Bravo

AF:

0.330

TwinsUK

AF:

0.304

AC:

1128

ALSPAC

AF:

0.313

AC:

1208

ESP6500AA

AF:

0.181

AC:

654

ESP6500EA

AF:

0.293

AC:

2170

ExAC

AF:

0.368

AC:

40613

Asia WGS

AF:

0.624

AC:

2167

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Greig cephalopolysyndactyly syndrome

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

not provided

Benign:2

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: 22984994, 24278334, 17029207) -

May 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pallister-Hall syndrome

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polysyndactyly 4

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polydactyly, postaxial, type A1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polydactyly

Benign:1

Mar 06, 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

0.057

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Uncertain

0.69

D;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

N;.

PhyloP100

5.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-4.1

D;.

REVEL

Benign

0.16

Sift

Benign

0.42

T;.

Sift4G

Benign

0.31

T;.

Polyphen

0.0010

B;.

Vest4

0.023

MPC

0.30

ClinPred

0.042

GERP RS

3.8

Varity_R

0.054

gMVP

0.30

Mutation Taster

=99/1

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