rs61758978

Positions:

• chr7-41966238-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000168.6(GLI3):​c.2835G>C​(p.Leu945=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,608,778 control chromosomes in the GnomAD database, including 598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (41 hom., cov: 33)
  • Exomes 𝑓: 0.026 (557 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.498

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-41966238-C-G is Benign according to our data. Variant chr7-41966238-C-G is described in ClinVar as [Benign]. Clinvar id is 194463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41966238-C-G is described in Lovd as [Benign]. Variant chr7-41966238-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.498 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0184 (2803/152310) while in subpopulation NFE AF= 0.0272 (1849/68010). AF 95% confidence interval is 0.0262. There are 41 homozygotes in gnomad4. There are 1272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.2835G>C	p.Leu945=	synonymous_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.2835G>C	p.Leu945=	synonymous_variant	15/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2802 AN: 152194 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0256

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0195 AC: 4548 AN: 232916 Hom.: 74 AF XY: 0.0205 AC XY: 2629 AN XY: 128150

Gnomad AFR exome AF: 0.00423

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0317

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.0174

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0259 AC: 37684 AN: 1456468 Hom.: 557 Cov.: 35 AF XY: 0.0257 AC XY: 18627 AN XY: 724822

Gnomad4 AFR exome AF: 0.00452

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.0198

Gnomad4 NFE exome AF: 0.0288

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0184 AC: 2803 AN: 152310 Hom.: 41 Cov.: 33 AF XY: 0.0171 AC XY: 1272 AN XY: 74472

Gnomad4 AFR AF: 0.00531

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0272

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0241 Hom.: 21

Bravo AF: 0.0186

Asia WGS AF: 0.0100 AC: 35 AN: 3472

EpiCase AF: 0.0260

EpiControl AF: 0.0266

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Nov 29, 2023	- -

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Greig cephalopolysyndactyly syndrome 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. -

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. -

Pallister-Hall syndrome 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	-0.42
CADD	Benign	8.1
DANN	Benign	0.74

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: rs61758978; hg19: chr7-42005836;