rs61758978

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000168.6(GLI3):c.2835G>C(p.Leu945Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,608,778 control chromosomes in the GnomAD database, including 598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 33)

Exomes 𝑓: 0.026 ( 557 hom. )

Consequence

GLI3
NM_000168.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.498

Publications

6 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: Ambry Genetics, G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
Pallister-Hall syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
polydactyly, postaxial, type A1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
polysyndactyly 4
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-41966238-C-G is Benign according to our data. Variant chr7-41966238-C-G is described in ClinVar as Benign. ClinVar VariationId is 194463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.498 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0184 (2803/152310) while in subpopulation NFE AF = 0.0272 (1849/68010). AF 95% confidence interval is 0.0262. There are 41 homozygotes in GnomAd4. There are 1272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AD,AR gene

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.2835G>C	p.Leu945Leu	synonymous	Exon 15 of 15	NP_000159.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLI3	ENST00000395925.8	TSL:5 MANE Select	c.2835G>C	p.Leu945Leu	synonymous	Exon 15 of 15	ENSP00000379258.3	P10071
GLI3	ENST00000677605.1		c.2835G>C	p.Leu945Leu	synonymous	Exon 15 of 15	ENSP00000503743.1	P10071
GLI3	ENST00000678429.1		c.2835G>C	p.Leu945Leu	synonymous	Exon 15 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2802

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.0256

Gnomad NFE

AF:

0.0272

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0195

AC:

4548

AN:

232916

AF XY:

0.0205

show subpopulations

Gnomad AFR exome

AF:

0.00423

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0317

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.0178

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0259

AC:

37684

AN:

1456468

Hom.:

557

Cov.:

AF XY:

0.0257

AC XY:

18627

AN XY:

724822

show subpopulations

African (AFR)

AF:

0.00452

AC:

151

AN:

33440

American (AMR)

AF:

0.0149

AC:

667

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

811

AN:

26056

East Asian (EAS)

AF:

0.000151

AC:

AN:

39652

South Asian (SAS)

AF:

0.0167

AC:

1436

AN:

86162

European-Finnish (FIN)

AF:

0.0198

AC:

979

AN:

49536

Middle Eastern (MID)

AF:

0.0295

AC:

170

AN:

5758

European-Non Finnish (NFE)

AF:

0.0288

AC:

32028

AN:

1111036

Other (OTH)

AF:

0.0239

AC:

1436

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2429

4858

7287

9716

12145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1208

2416

3624

4832

6040

<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:

0.0184

AC:

2803

AN:

152310

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1272

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00531

AC:

221

AN:

41586

American (AMR)

AF:

0.0174

AC:

266

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3468

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.0130

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0176

AC:

187

AN:

10630

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0272

AC:

1849

AN:

68010

Other (OTH)

AF:

0.0236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

155

310

464

619

774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0241

Hom.:

Bravo

AF:

0.0186

Asia WGS

AF:

0.0100

AC:

AN:

3472

EpiCase

AF:

0.0260

EpiControl

AF:

0.0266

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

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

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.1

(source)

DANN

Benign

0.74

PhyloP100

0.50

Mutation Taster

=100/0

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