7-42025253-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.305

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]

ACMG classification

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	UniProt
GLI3	NM_000168.6	c.1356+11G>C		intron_variant		ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.1356+11G>C		intron_variant		5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.972 AC: 147926 AN: 152192 Hom.: 71902 Cov.: 31

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

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.: 25 AF XY: 0.975 AC XY: 695273 AN XY: 713352

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.: 31 AF XY: 0.973 AC XY: 72498 AN XY: 74480

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

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Mar 03, 2015	- -
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	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

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

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

Other links and lift over

dbSNP: rs846273; hg19: chr7-42064852;