rs34020684

chr7-41978737-G-Achr7-41978737-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000168.6(GLI3):c.1509C>T(p.Asn503=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0493 in 1,612,408 control chromosomes in the GnomAD database, including 2,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (116 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2061 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.479

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-41978737-G-A is Benign according to our data. Variant chr7-41978737-G-A is described in ClinVar as [Benign]. Clinvar id is 255424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41978737-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.479 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.1509C>T	p.Asn503=	synonymous_variant	11/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.1509C>T	p.Asn503=	synonymous_variant	11/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5791 AN: 152128 Hom.: 115 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0529

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0373 AC: 9367 AN: 251394 Hom.: 207 AF XY: 0.0388 AC XY: 5272 AN XY: 135864

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.0219

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.0367

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0504

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0505 AC: 73671 AN: 1460162 Hom.: 2061 Cov.: 31 AF XY: 0.0503 AC XY: 36507 AN XY: 726506

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0420

Gnomad4 EAS exome AF: 0.00370

Gnomad4 SAS exome AF: 0.0364

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0565

Gnomad4 OTH exome AF: 0.0473

GnomAD4 genome AF: 0.0381 AC: 5793 AN: 152246 Hom.: 116 Cov.: 33 AF XY: 0.0361 AC XY: 2686 AN XY: 74434

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0453

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.0529

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0423 Hom.: 125

Bravo AF: 0.0368

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.0557

EpiControl AF: 0.0492

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Greig cephalopolysyndactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Pallister-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.56
Cadd	Benign	0.22
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34020684; hg19: chr7-42018336; COSMIC: COSV67890025; COSMIC: COSV67890025;