rs846266

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.547A>G(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 31372 hom., cov: 23)

Exomes 𝑓: 0.56 ( 235501 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.14

Publications

56 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=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 VariationId is 255446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000168.6. 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
	GLI3	NM_000168.6	MANE Select	c.547A>G	p.Thr183Ala	missense	Exon 5 of 15	NP_000159.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI3	ENST00000395925.8	TSL:5 MANE Select	c.547A>G	p.Thr183Ala	missense	Exon 5 of 15	ENSP00000379258.3
GLI3	ENST00000677605.1		c.547A>G	p.Thr183Ala	missense	Exon 5 of 15	ENSP00000503743.1
GLI3	ENST00000678429.1		c.547A>G	p.Thr183Ala	missense	Exon 5 of 15	ENSP00000502957.1

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

93747

AN:

147998

Hom.:

31332

Cov.:

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

GnomAD2 exomes

AF:

0.544

AC:

136825

AN:

251422

AF XY:

0.543

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 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.:

AF XY:

0.560

AC XY:

407017

AN XY:

726358

show subpopulations

African (AFR)

AF:

0.873

AC:

29190

AN:

33452

American (AMR)

AF:

0.368

AC:

16446

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.425

AC:

11110

AN:

26120

East Asian (EAS)

AF:

0.578

AC:

22960

AN:

39692

South Asian (SAS)

AF:

0.476

AC:

41076

AN:

86216

European-Finnish (FIN)

AF:

0.591

AC:

31543

AN:

53416

Middle Eastern (MID)

AF:

0.430

AC:

2474

AN:

5758

European-Non Finnish (NFE)

AF:

0.571

AC:

633962

AN:

1110034

Other (OTH)

AF:

0.552

AC:

33301

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

18534

37068

55601

74135

92669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17528

35056

52584

70112

87640

<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:

0.634

AC:

93840

AN:

148116

Hom.:

31372

Cov.:

AF XY:

0.626

AC XY:

45019

AN XY:

71922

show subpopulations

African (AFR)

AF:

0.865

AC:

34441

AN:

39834

American (AMR)

AF:

0.453

AC:

6629

AN:

14624

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1418

AN:

3444

East Asian (EAS)

AF:

0.568

AC:

2851

AN:

5020

South Asian (SAS)

AF:

0.469

AC:

2113

AN:

4510

European-Finnish (FIN)

AF:

0.589

AC:

5967

AN:

10130

Middle Eastern (MID)

AF:

0.408

AC:

119

AN:

292

European-Non Finnish (NFE)

AF:

0.574

AC:

38657

AN:

67340

Other (OTH)

AF:

0.562

AC:

1136

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1502

3004

4505

6007

7509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.580

Hom.:

88546

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (2)

Greig cephalopolysyndactyly syndrome (1)

Pallister-Hall syndrome (1)

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)

Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.24

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.027

MetaRNN

Benign

5.7e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.69

PhyloP100

3.1

PrimateAI

Benign

0.35

PROVEAN

Benign

2.1

REVEL

Benign

0.071

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.026

MPC

0.13

ClinPred

0.0017

GERP RS

3.2

Varity_R

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over