7-42190347-C-T

Variant names:

• chr7-42190347-C-T
• rs10951671
• NM_000168.6:c.124+32783G>A

Variant summary

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

The NM_000168.6(GLI3):​c.124+32783G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,056 control chromosomes in the GnomAD database, including 2,093 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 0.15 (2093 hom., cov: 32)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• Publications: 3 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6	c.124+32783G>A		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.124+32783G>A		intron_variant	Intron 2 of 14	5	NM_000168.6	ENSP00000379258.3
GLI3	ENST00000677605.1	c.124+32783G>A		intron_variant	Intron 2 of 14			ENSP00000503743.1
GLI3	ENST00000678429.1	c.124+32783G>A		intron_variant	Intron 2 of 14			ENSP00000502957.1
GLI3	ENST00000437480.1	c.125-17661G>A		intron_variant	Intron 2 of 2	2		ENSP00000407963.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22073 AN: 151940 Hom.: 2093 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.00713

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.145 AC: 22071 AN: 152056 Hom.: 2093 Cov.: 32 AF XY: 0.141 AC XY: 10502 AN XY: 74324

African (AFR) AF: 0.0424 AC: 1760 AN: 41496

American (AMR) AF: 0.136 AC: 2078 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 605 AN: 3462

East Asian (EAS) AF: 0.00714 AC: 37 AN: 5180

South Asian (SAS) AF: 0.146 AC: 701 AN: 4812

European-Finnish (FIN) AF: 0.167 AC: 1764 AN: 10568

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14650 AN: 67950

Other (OTH) AF: 0.142 AC: 299 AN: 2110

Alfa AF: 0.196 Hom.: 4259

Bravo AF: 0.138

Asia WGS AF: 0.0680 AC: 240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.045
DANN	Benign	0.44
PhyloP100		-2.4
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: rs10951671; hg19: chr7-42229946;