rs2237425

Variant names:

• chr7-42027757-C-G
• rs2237425
• NM_000168.6:c.1029-1345G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-42027757-C-G
• chr7-42027757-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000168.6(GLI3):​c.1029-1345G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,168 control chromosomes in the GnomAD database, including 1,858 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 0.14 (1858 hom., cov: 32)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000168.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	NM_000168.6	MANE Select	c.1029-1345G>C		intron	N/A	NP_000159.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	ENST00000395925.8	TSL:5 MANE Select	c.1029-1345G>C		intron	N/A	ENSP00000379258.3
	GLI3	ENST00000677605.1		c.1029-1345G>C		intron	N/A	ENSP00000503743.1
	GLI3	ENST00000678429.1		c.1029-1345G>C		intron	N/A	ENSP00000502957.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20956 AN: 152050 Hom.: 1859 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.138 AC: 20956 AN: 152168 Hom.: 1858 Cov.: 32 AF XY: 0.141 AC XY: 10451 AN XY: 74366

African (AFR) AF: 0.0424 AC: 1760 AN: 41546

American (AMR) AF: 0.135 AC: 2062 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2040 AN: 5168

South Asian (SAS) AF: 0.194 AC: 932 AN: 4814

European-Finnish (FIN) AF: 0.188 AC: 1986 AN: 10568

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11183 AN: 67994

Other (OTH) AF: 0.150 AC: 318 AN: 2116

Alfa AF: 0.140 Hom.: 228

Bravo AF: 0.130

Asia WGS AF: 0.262 AC: 909 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.71
PhyloP100		1.8
Mutation Taster		=99/1	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: rs2237425; hg19: chr7-42067356;