chr7-42026264-T-C

Variant names:

• chr7-42026264-T-C
• rs1380213537
• NM_000168.6:c.1177A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000168.6(GLI3):​c.1177A>G​(p.Ile393Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• Publications: 0 publications found

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]

GLI3 Gene-Disease associations (from GenCC):

• Greig cephalopolysyndactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Pallister-Hall syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
• polydactyly, postaxial, type A1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• polysyndactyly 4

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• tibial hemimelia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acrocallosal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11968216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.1177A>G	p.Ile393Val	missense_variant	Exon 8 of 15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.1177A>G	p.Ile393Val	missense_variant	Exon 8 of 15	5	NM_000168.6	ENSP00000379258.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Uncertain:1

Jun 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 393 of the GLI3 protein (p.Ile393Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 459206). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLI3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N;.
PhyloP100		3.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.12	N;.
REVEL	Benign	0.082
Sift	Benign	0.30	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0040	B;.
Vest4		0.35
MutPred		0.17		Gain of phosphorylation at T398 (P = 0.2067);.;
MVP		0.23
MPC		0.19
ClinPred		0.61	D
GERP RS		4.8
Varity_R		0.098
gMVP		0.11
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1380213537; hg19: chr7-42065863;