Variant 7-42025253-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000168.6(GLI3):c.1356+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.975 in 1,582,426 control chromosomes in the GnomAD database, including 752,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71959 hom., cov: 31)

Exomes 𝑓: 0.98 ( 680206 hom. )

Consequence

GLI3
NM_000168.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.305

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 (BayesDel_noAF=-0.91).

BP6

Variant 7-42025253-C-G is Benign according to our data. Variant chr7-42025253-C-G is described in ClinVar as [Benign]. Clinvar id is 255420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42025253-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.1356+11G>C		intron_variant		ENST00000395925.8	NP_000159.3	P10071

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8 link	c.1356+11G>C		intron_variant		5	NM_000168.6	ENSP00000379258.3		P10071

Frequencies

GnomAD3 genomes

AF:

0.972

AC:

147926

AN:

152192

Hom.:

71902

Cov.:

show subpopulations

Gnomad AFR

AF:

0.959

Gnomad AMI

AF:

0.985

Gnomad AMR

AF:

0.981

Gnomad ASJ

AF:

0.962

Gnomad EAS

AF:

0.986

Gnomad SAS

AF:

0.955

Gnomad FIN

AF:

0.995

Gnomad MID

AF:

0.915

Gnomad NFE

AF:

0.975

Gnomad OTH

AF:

0.972

GnomAD3 exomes

AF:

0.975

AC:

244600

AN:

250862

Hom.:

119293

AF XY:

0.974

AC XY:

132063

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.960

Gnomad AMR exome

AF:

0.988

Gnomad ASJ exome

AF:

0.963

Gnomad EAS exome

AF:

0.985

Gnomad SAS exome

AF:

0.955

Gnomad FIN exome

AF:

0.994

Gnomad NFE exome

AF:

0.974

Gnomad OTH exome

AF:

0.975

GnomAD4 exome

AF:

0.975

AC:

1394704

AN:

1430116

Hom.:

680206

Cov.:

AF XY:

0.975

AC XY:

695273

AN XY:

713352

show subpopulations

Gnomad4 AFR exome

AF:

0.955

Gnomad4 AMR exome

AF:

0.987

Gnomad4 ASJ exome

AF:

0.962

Gnomad4 EAS exome

AF:

0.986

Gnomad4 SAS exome

AF:

0.957

Gnomad4 FIN exome

AF:

0.993

Gnomad4 NFE exome

AF:

0.976

Gnomad4 OTH exome

AF:

0.974

GnomAD4 genome

AF:

0.972

AC:

148042

AN:

152310

Hom.:

71959

Cov.:

AF XY:

0.973

AC XY:

72498

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.959

Gnomad4 AMR

AF:

0.981

Gnomad4 ASJ

AF:

0.962

Gnomad4 EAS

AF:

0.986

Gnomad4 SAS

AF:

0.955

Gnomad4 FIN

AF:

0.995

Gnomad4 NFE

AF:

0.975

Gnomad4 OTH

AF:

0.972

Alfa

AF:

0.975

Hom.:

7657

Bravo

AF:

0.971

Asia WGS

AF:

0.966

AC:

3359

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	Jan 13, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	Jan 13, 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

Labcorp Genetics (formerly Invitae), Labcorp

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

Jan 13, 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

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.044

DANN

Benign

0.37

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