rs79703713

chr7-41965989-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000168.6(GLI3):c.3084C>T(p.Ser1028=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,604,450 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.019 (327 hom.)
• Consequence: GLI3 NM_000168.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.52

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=-0.54).
• BP6: Variant 7-41965989-G-A is Benign according to our data. Variant chr7-41965989-G-A is described in ClinVar as [Benign]. Clinvar id is 137486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41965989-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1906/152296) while in subpopulation NFE AF= 0.0214 (1455/68002). AF 95% confidence interval is 0.0205. There are 21 homozygotes in gnomad4. There are 789 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1908 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.3084C>T	p.Ser1028=	synonymous_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.3084C>T	p.Ser1028=	synonymous_variant	15/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152178 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00465

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0124 AC: 2914 AN: 234230 Hom.: 30 AF XY: 0.0123 AC XY: 1586 AN XY: 128616

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00860

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00191

Gnomad FIN exome AF: 0.00692

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0193 AC: 28019 AN: 1452154 Hom.: 327 Cov.: 34 AF XY: 0.0188 AC XY: 13550 AN XY: 722546

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.00683

Gnomad4 ASJ exome AF: 0.00936

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00698

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0125 AC: 1906 AN: 152296 Hom.: 21 Cov.: 32 AF XY: 0.0106 AC XY: 789 AN XY: 74458

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0190 Hom.: 16

Bravo AF: 0.0126

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

- -

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	-0.54
Cadd	Benign	3.0
Dann	Benign	0.54

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: rs79703713; hg19: chr7-42005587; COSMIC: COSV67895404;