rs79049330

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000168.6(GLI3):c.3083G>T(p.Ser1028Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,604,554 control chromosomes in the GnomAD database, including 349 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1028S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 32)

Exomes 𝑓: 0.019 ( 328 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.31

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: 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=0.0055089593).

BP6

Variant 7-41965990-C-A is Benign according to our data. Variant chr7-41965990-C-A is described in ClinVar as Benign. ClinVar VariationId is 137485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0125 (1906/152264) while in subpopulation NFE AF = 0.0214 (1455/67990). AF 95% confidence interval is 0.0205. There are 21 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	NM_000168.6	MANE Select	c.3083G>T	p.Ser1028Ile	missense	Exon 15 of 15	NP_000159.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI3	ENST00000395925.8	TSL:5 MANE Select	c.3083G>T	p.Ser1028Ile	missense	Exon 15 of 15	ENSP00000379258.3
GLI3	ENST00000677605.1		c.3083G>T	p.Ser1028Ile	missense	Exon 15 of 15	ENSP00000503743.1
GLI3	ENST00000678429.1		c.3083G>T	p.Ser1028Ile	missense	Exon 15 of 15	ENSP00000502957.1

Frequencies

GnomAD3 genomes

AF:

0.0125

AC:

1908

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00916

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00451

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0124

AC:

2906

AN:

234352

AF XY:

0.0123

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.00655

Gnomad ASJ exome

AF:

0.00859

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00671

Gnomad NFE exome

AF:

0.0218

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0193

AC:

28016

AN:

1452290

Hom.:

328

Cov.:

AF XY:

0.0187

AC XY:

13547

AN XY:

722602

show subpopulations

African (AFR)

AF:

0.00374

AC:

125

AN:

33464

American (AMR)

AF:

0.00683

AC:

305

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00936

AC:

244

AN:

26072

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39676

South Asian (SAS)

AF:

0.00195

AC:

168

AN:

86156

European-Finnish (FIN)

AF:

0.00691

AC:

311

AN:

45034

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0233

AC:

25946

AN:

1111232

Other (OTH)

AF:

0.0139

AC:

836

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1584

3169

4753

6338

7922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

972

1944

2916

3888

4860

<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:

0.0125

AC:

1906

AN:

152264

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

789

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00462

AC:

192

AN:

41566

American (AMR)

AF:

0.00914

AC:

140

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00451

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0214

AC:

1455

AN:

67990

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

192

288

384

480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0193

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0193

AC:

166

ExAC

AF:

0.0122

AC:

1475

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0213

EpiControl

AF:

0.0206

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 (2)

Greig cephalopolysyndactyly syndrome (1)

Pallister-Hall syndrome (1)

Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.74

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

3.3

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.13

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.084

Vest4

0.033

MPC

0.53

ClinPred

0.065

GERP RS

0.26

Varity_R

0.27

gMVP

0.44

Mutation Taster

=97/3

polymorphism

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over