rs116195563
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000168.6(GLI3):c.1029-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,608,960 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0080 ( 18 hom., cov: 33)
Exomes 𝑓: 0.00079 ( 16 hom. )
Consequence
GLI3
NM_000168.6 splice_polypyrimidine_tract, intron
NM_000168.6 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001994
2
Clinical Significance
Conservation
PhyloP100: 0.00300
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 7-42026423-G-A is Benign according to our data. Variant chr7-42026423-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42026423-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00802 (1221/152204) while in subpopulation AFR AF= 0.0282 (1172/41496). AF 95% confidence interval is 0.0269. There are 18 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1221 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GLI3 | NM_000168.6 | c.1029-11C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000395925.8 | NP_000159.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GLI3 | ENST00000395925.8 | c.1029-11C>T | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000168.6 | ENSP00000379258 | P1 |
Frequencies
GnomAD3 genomes 0.00802 AC: 1219AN: 152086Hom.: 18 Cov.: 33
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GnomAD3 exomes AF: 0.00219 AC: 546AN: 249558Hom.: 6 AF XY: 0.00160 AC XY: 216AN XY: 134876
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GnomAD4 exome AF: 0.000792 AC: 1154AN: 1456756Hom.: 16 Cov.: 30 AF XY: 0.000639 AC XY: 463AN XY: 724944
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GnomAD4 genome 0.00802 AC: 1221AN: 152204Hom.: 18 Cov.: 33 AF XY: 0.00771 AC XY: 574AN XY: 74406
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Aug 11, 2015 | 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. - |
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. - |
Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome;C1868111:Polysyndactyly 4;C4282400:Polydactyly, postaxial, type A1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 21, 2022 | - - |
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. - |
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. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at