rs35488756

Variant names:

• chr7-42023572-C-G
• rs35488756
• NM_000168.6:c.1393G>C

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.1393G>C​(p.Gly465Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,320 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G465G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (24 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 6.06
• Publications: 15 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 (MetaRNN=0.00919497).
• BP6: Variant 7-42023572-C-G is Benign according to our data. Variant chr7-42023572-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255422.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 = 0.0033 (501/151884) while in subpopulation NFE AF = 0.00505 (343/67952). AF 95% confidence interval is 0.00461. There are 3 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1393G>C	p.Gly465Arg	missense	Exon 10 of 15	NP_000159.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI3	ENST00000395925.8	TSL:5 MANE Select	c.1393G>C	p.Gly465Arg	missense	Exon 10 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.1393G>C	p.Gly465Arg	missense	Exon 10 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.1393G>C	p.Gly465Arg	missense	Exon 10 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 501 AN: 151766 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00275

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00865

GnomAD2 exomes AF: 0.00393 AC: 988 AN: 251492 AF XY: 0.00412

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00606

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00399 AC: 5832 AN: 1461436 Hom.: 24 Cov.: 32 AF XY: 0.00416 AC XY: 3025 AN XY: 727050

African (AFR) AF: 0.000777 AC: 26 AN: 33472

American (AMR) AF: 0.00284 AC: 127 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00830 AC: 217 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86250

European-Finnish (FIN) AF: 0.00245 AC: 131 AN: 53416

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5768

European-Non Finnish (NFE) AF: 0.00433 AC: 4817 AN: 1111596

Other (OTH) AF: 0.00437 AC: 264 AN: 60382

GnomAD4 genome AF: 0.00330 AC: 501 AN: 151884 Hom.: 3 Cov.: 32 AF XY: 0.00317 AC XY: 235 AN XY: 74222

African (AFR) AF: 0.000386 AC: 16 AN: 41406

American (AMR) AF: 0.00314 AC: 48 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4792

European-Finnish (FIN) AF: 0.00275 AC: 29 AN: 10550

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.00505 AC: 343 AN: 67952

Other (OTH) AF: 0.00856 AC: 18 AN: 2104

Alfa AF: 0.00486 Hom.: 2

Bravo AF: 0.00336

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00440 AC: 534

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00753

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Greig cephalopolysyndactyly syndrome (2)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)
-	-	1	Polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Benign	0.39	T
Sift4G	Benign	0.079	T
Polyphen		0.017	B
Vest4		0.82
MutPred		0.27		Gain of solvent accessibility (P = 0.0971)
MVP		0.74
MPC		0.63
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.36
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35488756; hg19: chr7-42063171; COSMIC: COSV67884644;