rs121917713
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000168.6(GLI3):c.868C>T(p.Arg290Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GLI3
NM_000168.6 stop_gained
NM_000168.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.69
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-42040198-G-A is Pathogenic according to our data. Variant chr7-42040198-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42040198-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-42040198-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLI3 | NM_000168.6 | c.868C>T | p.Arg290Ter | stop_gained | 7/15 | ENST00000395925.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLI3 | ENST00000395925.8 | c.868C>T | p.Arg290Ter | stop_gained | 7/15 | 5 | NM_000168.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461754Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727196
GnomAD4 exome
AF:
AC:
1
AN:
1461754
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727196
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Greig cephalopolysyndactyly syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 24, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | Mar 24, 2022 | - - |
Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2016 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GLI3 are known to be pathogenic. This particular variant has been reported in the literature in individuals and families affected with preaxial polydactylytype-IV and Greig cephalopolysyndactyly syndrome (PMID: 15739154, 24736735, 15811011). This sequence change creates a premature translational stop signal at codon 290 (p.Arg290*) of the GLI3 gene. It is expected to result in an absent or disrupted protein product. - |
Polysyndactyly 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 24, 2008 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at