rs74536326

Variant names:

• chr7-42048700-G-A
• rs74536326
• NM_000168.6:c.474-4C>T

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.474-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,603,260 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: GLI3 NM_000168.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001710
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.323
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-42048700-G-A is Benign according to our data. Variant chr7-42048700-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000462 (69/149284) while in subpopulation EAS AF = 0.00941 (48/5100). AF 95% confidence interval is 0.00729. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	NM_000168.6	MANE Select	c.474-4C>T		splice_region 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.474-4C>T		splice_region intron	N/A	ENSP00000379258.3
	GLI3	ENST00000677605.1		c.474-4C>T		splice_region intron	N/A	ENSP00000503743.1
	GLI3	ENST00000678429.1		c.474-4C>T		splice_region intron	N/A	ENSP00000502957.1

Frequencies

GnomAD3 genomes AF: 0.000463 AC: 69 AN: 149166 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.00939

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000888

Gnomad OTH AF: 0.000992

GnomAD2 exomes AF: 0.000970 AC: 240 AN: 247452 AF XY: 0.00102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00893

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000678 AC: 986 AN: 1453976 Hom.: 8 Cov.: 30 AF XY: 0.000669 AC XY: 484 AN XY: 723630

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.0000225 AC: 1 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26068

East Asian (EAS) AF: 0.0162 AC: 640 AN: 39590

South Asian (SAS) AF: 0.00152 AC: 131 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5750

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1105332

Other (OTH) AF: 0.000698 AC: 42 AN: 60162

GnomAD4 genome AF: 0.000462 AC: 69 AN: 149284 Hom.: 0 Cov.: 26 AF XY: 0.000509 AC XY: 37 AN XY: 72648

African (AFR) AF: 0.00 AC: 0 AN: 40342

American (AMR) AF: 0.00 AC: 0 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3452

East Asian (EAS) AF: 0.00941 AC: 48 AN: 5100

South Asian (SAS) AF: 0.00153 AC: 7 AN: 4562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000888 AC: 6 AN: 67558

Other (OTH) AF: 0.000981 AC: 2 AN: 2038

Alfa AF: 0.000297 Hom.: 1

Bravo AF: 0.000397

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	1	not provided (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	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)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.4
DANN	Benign	0.67
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.070		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: rs74536326; hg19: chr7-42088299; COSMIC: COSV67893009;