rs121917710

chr7-41967848-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000168.6(GLI3):c.2179G>A(p.Gly727Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00635 in 1,614,096 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 51 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 5.65

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008583009).

BP6

Variant 7-41967848-C-T is Benign according to our data. Variant chr7-41967848-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 13821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41967848-C-T is described in Lovd as [Likely_benign]. Variant chr7-41967848-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd at 772 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6 linkuse as main transcript	c.2179G>A	p.Gly727Arg	missense_variant	14/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8 linkuse as main transcript	c.2179G>A	p.Gly727Arg	missense_variant	14/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00508

AC:

772

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00820

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00527

AC:

1325

AN:

251488

Hom.:

AF XY:

0.00556

AC XY:

756

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00572

Gnomad FIN exome

AF:

0.00762

Gnomad NFE exome

AF:

0.00755

Gnomad OTH exome

AF:

0.00521

GnomAD4 exome

AF:

0.00649

AC:

9484

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00660

AC XY:

4797

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00272

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00579

Gnomad4 FIN exome

AF:

0.00766

Gnomad4 NFE exome

AF:

0.00722

Gnomad4 OTH exome

AF:

0.00528

GnomAD4 genome

AF:

0.00506

AC:

771

AN:

152228

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

382

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.0107

Gnomad4 NFE

AF:

0.00819

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00646

Hom.:

Bravo

AF:

0.00392

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00571

AC:

693

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00665

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2018	This variant is associated with the following publications: (PMID: 10441570, 25527561, 31325247, 32696176) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GLI3: BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2014	- -

Postaxial polydactyly, type A1/B

Uncertain:1

Uncertain significance, flagged submission

literature only

OMIM

Sep 01, 1999

- -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Postaxial polydactyly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 10, 2023

- -

Greig cephalopolysyndactyly syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Polydactyly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pallister-Hall syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.3

D;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.013

D;.

Sift4G

Benign

0.092

T;.

Polyphen

0.99

D;.

Vest4

0.94

MutPred

0.79

Loss of glycosylation at S726 (P = 0.0404);.;

MVP

0.87

MPC

1.1

ClinPred

0.036

GERP RS

5.8

Varity_R

0.68

gMVP

0.56

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