rs118149040

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3664C>T(p.Pro1222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,609,668 control chromosomes in the GnomAD database, including 6 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 5 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.10

Publications

10 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, G2P
Pallister-Hall syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
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=0.006187767).

BP6

Variant 7-41965409-G-A is Benign according to our data. Variant chr7-41965409-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00243 (370/152276) while in subpopulation AMR AF = 0.00405 (62/15306). AF 95% confidence interval is 0.00324. There are 1 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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.3664C>T	p.Pro1222Ser	missense	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.3664C>T	p.Pro1222Ser	missense	Exon 15 of 15	ENSP00000379258.3	P10071
GLI3	ENST00000677605.1		c.3664C>T	p.Pro1222Ser	missense	Exon 15 of 15	ENSP00000503743.1	P10071
GLI3	ENST00000678429.1		c.3664C>T	p.Pro1222Ser	missense	Exon 15 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes

AF:

0.00243

AC:

370

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00273

AC:

681

AN:

249474

AF XY:

0.00266

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00567

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00306

AC:

4464

AN:

1457392

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

2187

AN XY:

724512

show subpopulations

African (AFR)

AF:

0.000479

AC:

AN:

33414

American (AMR)

AF:

0.00264

AC:

118

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

158

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.000337

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00198

AC:

102

AN:

51644

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00343

AC:

3812

AN:

1109900

Other (OTH)

AF:

0.00321

AC:

193

AN:

60190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

259

517

776

1034

1293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00243

AC:

370

AN:

152276

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41556

American (AMR)

AF:

0.00405

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00347

AC:

236

AN:

68014

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00336

Hom.:

Bravo

AF:

0.00257

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00284

AC:

345

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00522

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Greig cephalopolysyndactyly syndrome (1)

Inborn genetic diseases (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

0.056

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0020

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.29

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

PhyloP100

-2.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

REVEL

Benign

0.027

Sift

Benign

0.83

Sift4G

Benign

0.80

Polyphen

0.0

Vest4

0.018

MVP

0.12

MPC

0.29

ClinPred

0.0031

GERP RS

-11

Varity_R

0.019

gMVP

0.032

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over