rs121917712

Positions:

• chr7-41972567-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000168.6(GLI3):​c.1873C>T​(p.Arg625Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R625Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.52

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-41972566-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 7-41972567-G-A is Pathogenic according to our data. Variant chr7-41972567-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13824.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-41972567-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI3	NM_000168.6	c.1873C>T	p.Arg625Trp	missense_variant	13/15	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.1873C>T	p.Arg625Trp	missense_variant	13/15	5	NM_000168.6	ENSP00000379258	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Greig cephalopolysyndactyly syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 0.62). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GLI3 -related disorder (ClinVar ID: VCV000013824 / PMID: 15739154). However, the evidence of pathogenicity is insufficient at this time. A different missense change at the same codon (p.Arg625Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000528805). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.86		Loss of catalytic residue at R625 (P = 0.0065);.;
MVP		0.84
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.81

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: rs121917712; hg19: chr7-42012166; COSMIC: COSV67887574;