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GeneBe

rs61758978

chr7-41966238-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.498
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.498 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
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. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 2802 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLI3NM_000168.6 linkuse as main transcriptc.2835G>C p.Leu945= synonymous_variant 15/15 ENST00000395925.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLI3ENST00000395925.8 linkuse as main transcriptc.2835G>C p.Leu945= synonymous_variant 15/155 NM_000168.6 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0184
AC:
2802
AN:
152194
Hom.:
41
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0184
AC:
2803
AN:
152310
Hom.:
41
Cov.:
33
AF XY:
0.0171
AC XY:
1272
AN XY:
74472
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 20, 2015- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Greig cephalopolysyndactyly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61758978; hg19: chr7-42005836; API