rs2049622

Variant names:

• chr7-42136683-G-A
• rs2049622
• NM_000168.6:c.367+11543C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-42136683-G-A
• chr7-42136683-G-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.367+11543C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 152,122 control chromosomes in the GnomAD database, including 17,098 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 0.46 (17098 hom., cov: 33)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 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+11543C>T		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+11543C>T		intron	N/A	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.367+11543C>T		intron	N/A	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.367+11543C>T		intron	N/A	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69381 AN: 152006 Hom.: 17102 Cov.: 33

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.456 AC: 69390 AN: 152122 Hom.: 17098 Cov.: 33 AF XY: 0.464 AC XY: 34540 AN XY: 74364

African (AFR) AF: 0.261 AC: 10826 AN: 41480

American (AMR) AF: 0.544 AC: 8331 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1748 AN: 3470

East Asian (EAS) AF: 0.644 AC: 3329 AN: 5166

South Asian (SAS) AF: 0.612 AC: 2953 AN: 4824

European-Finnish (FIN) AF: 0.577 AC: 6103 AN: 10580

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.505 AC: 34332 AN: 67982

Other (OTH) AF: 0.499 AC: 1055 AN: 2114

Alfa AF: 0.481 Hom.: 33403

Bravo AF: 0.443

Asia WGS AF: 0.656 AC: 2278 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.52
PhyloP100		-0.23
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: rs2049622; hg19: chr7-42176282;