7-41966247-C-G

Variant names:

• chr7-41966247-C-G
• rs34245321
• NM_000168.6:c.2826G>C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000168.6(GLI3):​c.2826G>C​(p.Pro942Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,608,140 control chromosomes in the GnomAD database, including 2,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (110 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2125 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.703

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=-0.41).
• BP6: Variant 7-41966247-C-G is Benign according to our data. Variant chr7-41966247-C-G is described in ClinVar as [Benign]. Clinvar id is 194461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41966247-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.703 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.2826G>C	p.Pro942Pro	synonymous_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.2826G>C	p.Pro942Pro	synonymous_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5331 AN: 152184 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0430

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0532

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0373 AC: 8642 AN: 231746 Hom.: 195 AF XY: 0.0396 AC XY: 5060 AN XY: 127766

Gnomad AFR exome AF: 0.00973

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0435

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.0457

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0505

Gnomad OTH exome AF: 0.0394

GnomAD4 exome AF: 0.0513 AC: 74624 AN: 1455840 Hom.: 2125 Cov.: 35 AF XY: 0.0513 AC XY: 37184 AN XY: 724548

Gnomad4 AFR exome AF: 0.00978

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0573

Gnomad4 OTH exome AF: 0.0474

GnomAD4 genome AF: 0.0350 AC: 5329 AN: 152300 Hom.: 110 Cov.: 33 AF XY: 0.0330 AC XY: 2456 AN XY: 74464

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0427

Gnomad4 FIN AF: 0.0305

Gnomad4 NFE AF: 0.0532

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0342 Hom.: 48

Bravo AF: 0.0328

EpiCase AF: 0.0559

EpiControl AF: 0.0498

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Oct 08, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Greig cephalopolysyndactyly syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pallister-Hall syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.41
CADD	Benign	9.5
DANN	Benign	0.78

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: rs34245321; hg19: chr7-42005845;