7-42134997-T-G

Variant names:

• chr7-42134997-T-G
• rs6974655
• NM_000168.6:c.367+13229A>C

Variant summary

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

The NM_000168.6(GLI3):​c.367+13229A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 151,980 control chromosomes in the GnomAD database, including 41,281 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 0.74 (41281 hom., cov: 31)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, G2P
• Pallister-Hall syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• 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=-0.28).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.801 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	NM_000168.6	MANE Select	c.367+13229A>C		intron	N/A	NP_000159.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	ENST00000395925.8	TSL:5 MANE Select	c.367+13229A>C		intron	N/A	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.367+13229A>C		intron	N/A	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.367+13229A>C		intron	N/A	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111795 AN: 151862 Hom.: 41250 Cov.: 31

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.755

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

GnomAD4 genome AF: 0.736 AC: 111879 AN: 151980 Hom.: 41281 Cov.: 31 AF XY: 0.739 AC XY: 54909 AN XY: 74298

African (AFR) AF: 0.720 AC: 29831 AN: 41406

American (AMR) AF: 0.813 AC: 12419 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2463 AN: 3468

East Asian (EAS) AF: 0.759 AC: 3918 AN: 5160

South Asian (SAS) AF: 0.714 AC: 3437 AN: 4816

European-Finnish (FIN) AF: 0.757 AC: 7988 AN: 10556

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49318 AN: 67982

Other (OTH) AF: 0.756 AC: 1599 AN: 2116

Alfa AF: 0.733 Hom.: 69235

Bravo AF: 0.739

Asia WGS AF: 0.775 AC: 2696 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		2.7
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: rs6974655; hg19: chr7-42174596;