chr7-41965053-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000168.6(GLI3):c.4020C>T(p.Pro1340Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,613,830 control chromosomes in the GnomAD database, including 2,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1340P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 106 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2127 hom. )

Consequence

GLI3
NM_000168.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.41

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-41965053-G-A is Benign according to our data. Variant chr7-41965053-G-A is described in ClinVar as Benign. ClinVar VariationId is 255441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.41 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0517 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.4020C>T	p.Pro1340Pro	synonymous	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.4020C>T	p.Pro1340Pro	synonymous	Exon 15 of 15	ENSP00000379258.3
GLI3	ENST00000677605.1		c.4020C>T	p.Pro1340Pro	synonymous	Exon 15 of 15	ENSP00000503743.1
GLI3	ENST00000678429.1		c.4020C>T	p.Pro1340Pro	synonymous	Exon 15 of 15	ENSP00000502957.1

Frequencies

GnomAD3 genomes

AF:

0.0346

AC:

5266

AN:

152204

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0100

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0430

Gnomad FIN

AF:

0.0304

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0531

Gnomad OTH

AF:

0.0387

GnomAD2 exomes

AF:

0.0372

AC:

9318

AN:

250552

AF XY:

0.0395

show subpopulations

Gnomad AFR exome

AF:

0.00819

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0433

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0504

Gnomad OTH exome

AF:

0.0385

GnomAD4 exome

AF:

0.0511

AC:

74715

AN:

1461508

Hom.:

2127

Cov.:

AF XY:

0.0512

AC XY:

37214

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00798

AC:

267

AN:

33478

American (AMR)

AF:

0.0222

AC:

991

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0423

AC:

1105

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0458

AC:

3954

AN:

86254

European-Finnish (FIN)

AF:

0.0316

AC:

1679

AN:

53104

Middle Eastern (MID)

AF:

0.0394

AC:

227

AN:

5768

European-Non Finnish (NFE)

AF:

0.0572

AC:

63632

AN:

1111958

Other (OTH)

AF:

0.0473

AC:

2854

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4497

8993

13490

17986

22483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2408

4816

7224

9632

12040

<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:

0.0346

AC:

5263

AN:

152322

Hom.:

106

Cov.:

AF XY:

0.0327

AC XY:

2432

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00998

AC:

415

AN:

41588

American (AMR)

AF:

0.0278

AC:

426

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0427

AC:

206

AN:

4830

European-Finnish (FIN)

AF:

0.0304

AC:

323

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0531

AC:

3612

AN:

68016

Other (OTH)

AF:

0.0383

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

269

538

807

1076

1345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0359

Hom.:

Bravo

AF:

0.0321

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.0555

EpiControl

AF:

0.0493

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Greig cephalopolysyndactyly syndrome (1)

not provided (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

-0.81

CADD

Benign

0.084

(source)

DANN

Benign

0.50

PhyloP100

-1.4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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