rs79879393

Variant names:

• chr7-42076876-C-T
• rs79879393
• NM_000168.6:c.368-19G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000168.6(GLI3):​c.368-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,417,012 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (92 hom.)
• Consequence: GLI3 NM_000168.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.405
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-42076876-C-T is Benign according to our data. Variant chr7-42076876-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00844 (1284/152212) while in subpopulation NFE AF = 0.0111 (752/68000). AF 95% confidence interval is 0.0104. There are 11 homozygotes in GnomAd4. There are 601 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

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.368-19G>A		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.368-19G>A		intron	N/A	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.368-19G>A		intron	N/A	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.368-19G>A		intron	N/A	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1285 AN: 152094 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00956 AC: 2393 AN: 250190 AF XY: 0.00943

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.00659

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0105 AC: 13313 AN: 1264800 Hom.: 92 Cov.: 19 AF XY: 0.0104 AC XY: 6677 AN XY: 639508

African (AFR) AF: 0.00212 AC: 63 AN: 29720

American (AMR) AF: 0.00735 AC: 327 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 1162 AN: 24912

East Asian (EAS) AF: 0.00 AC: 0 AN: 38782

South Asian (SAS) AF: 0.00283 AC: 233 AN: 82258

European-Finnish (FIN) AF: 0.00587 AC: 313 AN: 53350

Middle Eastern (MID) AF: 0.00931 AC: 50 AN: 5372

European-Non Finnish (NFE) AF: 0.0113 AC: 10568 AN: 932064

Other (OTH) AF: 0.0111 AC: 597 AN: 53876

GnomAD4 genome AF: 0.00844 AC: 1284 AN: 152212 Hom.: 11 Cov.: 32 AF XY: 0.00807 AC XY: 601 AN XY: 74432

African (AFR) AF: 0.00246 AC: 102 AN: 41524

American (AMR) AF: 0.00968 AC: 148 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 164 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.00726 AC: 77 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 752 AN: 68000

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0144 Hom.: 8

Bravo AF: 0.00857

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome;C1868111:Polysyndactyly 4;C4282400:Polydactyly, postaxial, type A1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.23
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism

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: rs79879393; hg19: chr7-42116475;