rs886062336

chr7-41966331-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000168.6(GLI3):c.2741del(p.Gly914AlafsTer38) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLI3 NM_000168.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 55 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI3	NM_000168.6	c.2741del	p.Gly914AlafsTer38	frameshift_variant	15/15	ENST00000395925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI3	ENST00000395925.8	c.2741del	p.Gly914AlafsTer38	frameshift_variant	15/15	5	NM_000168.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

GLI3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The GLI3 c.2741delG (p.Gly914AlafsTer38) variant causes a frameshift and is predicted to result in a premature termination of the protein. The p.Gly914AlafsTer38 variant has been reported in one study, where it was found in a heterozygous state in an individual with Greig cephalopolysyndactyly who manifested postaxial polydactyly with macrocephaly and hypertelorism and had a family history of preaxial polydactyly (Johnston et al. 2010). A related affected individual was also heterozygous for the p.Gly914AlafsTer38 variant. Control data are unavailable for this variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium despite being located in a region of good sequencing coverage, suggesting that this is a rare variant. Due to the potential impact of frameshift variants and the available evidence, the p.Gly914AlafsTer38 variant is classified as a variant of unknown significance but is suspicious for pathogenicity for GLI3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

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: rs886062336; hg19: chr7-42005929;