7-41965244-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000168.6(GLI3):c.3829C>G(p.Gln1277Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1277R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.95

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019524276).

BP6

Variant 7-41965244-G-C is Benign according to our data. Variant chr7-41965244-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283570.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000381 (58/152212) while in subpopulation AFR AF = 0.00137 (57/41466). AF 95% confidence interval is 0.00109. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3829C>G	p.Gln1277Glu	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.3829C>G	p.Gln1277Glu	missense	Exon 15 of 15	ENSP00000379258.3
GLI3	ENST00000677605.1		c.3829C>G	p.Gln1277Glu	missense	Exon 15 of 15	ENSP00000503743.1
GLI3	ENST00000678429.1		c.3829C>G	p.Gln1277Glu	missense	Exon 15 of 15	ENSP00000502957.1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000120

AC:

AN:

250318

AF XY:

0.0000960

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461474

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111850

Other (OTH)

AF:

0.000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000381

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41466

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

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:

0.000113

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 09, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 17, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Dec 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome

Benign:1

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Feb 03, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.39

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

M_CAP

Benign

0.0075

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

2.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

REVEL

Benign

0.069

Sift

Uncertain

0.0060

Sift4G

Benign

0.35

Polyphen

0.020

Vest4

0.40

MVP

0.42

MPC

0.33

ClinPred

0.039

GERP RS

4.9

Varity_R

0.17

gMVP

0.12

Mutation Taster

=84/16

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over