rs3898405

Positions:

• chr7-42048633-G-A

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.537C>T​(p.His179=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,609,700 control chromosomes in the GnomAD database, including 6,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (509 hom., cov: 26)
  • Exomes 𝑓: 0.087 (6366 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.09

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 7-42048633-G-A is Benign according to our data. Variant chr7-42048633-G-A is described in ClinVar as [Benign]. Clinvar id is 255445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42048633-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.537C>T	p.His179=	synonymous_variant	5/15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.537C>T	p.His179=	synonymous_variant	5/15	5	NM_000168.6	ENSP00000379258	P1

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10344 AN: 149164 Hom.: 509 Cov.: 26

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0506

GnomAD3 exomes AF: 0.0680 AC: 17099 AN: 251374 Hom.: 783 AF XY: 0.0694 AC XY: 9424 AN XY: 135870

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0987

Gnomad OTH exome AF: 0.0653

GnomAD4 exome AF: 0.0870 AC: 127123 AN: 1460418 Hom.: 6366 Cov.: 33 AF XY: 0.0858 AC XY: 62354 AN XY: 726624

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0602

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.0989

Gnomad4 OTH exome AF: 0.0738

GnomAD4 genome AF: 0.0693 AC: 10346 AN: 149282 Hom.: 509 Cov.: 26 AF XY: 0.0685 AC XY: 4970 AN XY: 72604

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.0553

Gnomad4 ASJ AF: 0.0556

Gnomad4 EAS AF: 0.000393

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0505

Alfa AF: 0.0902 Hom.: 401

Bravo AF: 0.0591

Asia WGS AF: 0.0180 AC: 63 AN: 3476

EpiCase AF: 0.0914

EpiControl AF: 0.0856

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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 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	-0.42
CADD	Benign	6.6
DANN	Benign	0.71

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: rs3898405; hg19: chr7-42088232; COSMIC: COSV67890037;