rs929387

chr7-41966080-G-Achr7-41966080-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000168.6(GLI3):c.2993C>T(p.Pro998Leu) variant causes a missense change. The variant allele was found at a frequency of 0.346 in 1,567,904 control chromosomes in the GnomAD database, including 102,269 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P998R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.32 ( 9226 hom., cov: 32)

Exomes 𝑓: 0.35 ( 93043 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.99

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0673986E-6).

BP6

Variant 7-41966080-G-A is Benign according to our data. Variant chr7-41966080-G-A is described in ClinVar as [Benign]. Clinvar id is 255433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41966080-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6 linkuse as main transcript	c.2993C>T	p.Pro998Leu	missense_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8 linkuse as main transcript	c.2993C>T	p.Pro998Leu	missense_variant	15/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49128

AN:

151778

Hom.:

9209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.189

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.439

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.805

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.341

GnomAD3 exomes

AF:

0.425

AC:

74159

AN:

174410

Hom.:

17712

AF XY:

0.420

AC XY:

40780

AN XY:

97144

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.569

Gnomad ASJ exome

AF:

0.394

Gnomad EAS exome

AF:

0.788

Gnomad SAS exome

AF:

0.468

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.388

GnomAD4 exome

AF:

0.348

AC:

493056

AN:

1416008

Hom.:

93043

Cov.:

AF XY:

0.351

AC XY:

246594

AN XY:

701882

show subpopulations

Gnomad4 AFR exome

AF:

0.189

Gnomad4 AMR exome

AF:

0.551

Gnomad4 ASJ exome

AF:

0.396

Gnomad4 EAS exome

AF:

0.819

Gnomad4 SAS exome

AF:

0.465

Gnomad4 FIN exome

AF:

0.326

Gnomad4 NFE exome

AF:

0.319

Gnomad4 OTH exome

AF:

0.363

GnomAD4 genome

AF:

0.324

AC:

49176

AN:

151896

Hom.:

9226

Cov.:

AF XY:

0.331

AC XY:

24603

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.189

Gnomad4 AMR

AF:

0.440

Gnomad4 ASJ

AF:

0.409

Gnomad4 EAS

AF:

0.805

Gnomad4 SAS

AF:

0.492

Gnomad4 FIN

AF:

0.336

Gnomad4 NFE

AF:

0.324

Gnomad4 OTH

AF:

0.347

Alfa

AF:

0.307

Hom.:

2959

Bravo

AF:

0.330

TwinsUK

AF:

0.304

AC:

1128

ALSPAC

AF:

0.313

AC:

1208

ESP6500AA

AF:

0.181

AC:

654

ESP6500EA

AF:

0.293

AC:

2170

ExAC

AF:

0.368

AC:

40613

Asia WGS

AF:

0.624

AC:

2167

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Greig cephalopolysyndactyly syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22984994, 24278334, 17029207) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 20, 2020	- -

Pallister-Hall syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Polysyndactyly 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Polydactyly, postaxial, type A1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Polydactyly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

Cadd

Benign

Dann

Benign

0.68

DEOGEN2

Uncertain

0.69

D;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

N;.

MutationTaster

Benign

0.084

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-4.1

D;.

REVEL

Benign

0.16

Sift

Benign

0.42

T;.

Sift4G

Benign

0.31

T;.

Polyphen

0.0010

B;.

Vest4

0.023

MPC

0.30

ClinPred

0.042

GERP RS

3.8

Varity_R

0.054

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over