rs2286294

Variant names:

• chr7-42172250-A-G
• rs2286294
• NM_000168.6:c.125-23782T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000168.6(GLI3):​c.125-23782T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 151,384 control chromosomes in the GnomAD database, including 16,900 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (16900 hom., cov: 30)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.125-23782T>C		intron_variant	Intron 2 of 14	ENST00000395925.8	NP_000159.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI3	ENST00000395925.8	c.125-23782T>C		intron_variant	Intron 2 of 14	5	NM_000168.6	ENSP00000379258.3
GLI3	ENST00000677605.1	c.125-23782T>C		intron_variant	Intron 2 of 14			ENSP00000503743.1
GLI3	ENST00000678429.1	c.125-23782T>C		intron_variant	Intron 2 of 14			ENSP00000502957.1
GLI3	ENST00000437480.1	c.*270T>C		downstream_gene_variant		2		ENSP00000407963.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70713 AN: 151262 Hom.: 16875 Cov.: 30

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.424

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.468 AC: 70778 AN: 151384 Hom.: 16900 Cov.: 30 AF XY: 0.462 AC XY: 34180 AN XY: 73914

African (AFR) AF: 0.543 AC: 22406 AN: 41260

American (AMR) AF: 0.430 AC: 6544 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1415 AN: 3462

East Asian (EAS) AF: 0.169 AC: 852 AN: 5040

South Asian (SAS) AF: 0.436 AC: 2080 AN: 4772

European-Finnish (FIN) AF: 0.418 AC: 4386 AN: 10482

Middle Eastern (MID) AF: 0.407 AC: 118 AN: 290

European-Non Finnish (NFE) AF: 0.468 AC: 31762 AN: 67832

Other (OTH) AF: 0.421 AC: 884 AN: 2102

Alfa AF: 0.464 Hom.: 24616

Bravo AF: 0.469

Asia WGS AF: 0.333 AC: 1157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.84
DANN	Benign	0.73
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2286294; hg19: chr7-42211849;