rs35280470

Variant names:

• chr7-41965066-C-T
• rs35280470
• NM_000168.6:c.4007G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-41965066-C-T
• chr7-41965066-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000168.6(GLI3):​c.4007G>A​(p.Gly1336Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,613,792 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1336G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (103 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2042 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0960
• 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=0.002038449).
• BP6: Variant 7-41965066-C-T is Benign according to our data. Variant chr7-41965066-C-T is described in ClinVar as Benign. ClinVar VariationId is 255440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 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.4007G>A	p.Gly1336Glu	missense	Exon 15 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.4007G>A	p.Gly1336Glu	missense	Exon 15 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.4007G>A	p.Gly1336Glu	missense	Exon 15 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.4007G>A	p.Gly1336Glu	missense	Exon 15 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.0340 AC: 5172 AN: 152194 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0353 AC: 8849 AN: 250488 AF XY: 0.0369

Gnomad AFR exome AF: 0.00845

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0372

GnomAD4 exome AF: 0.0501 AC: 73164 AN: 1461480 Hom.: 2042 Cov.: 34 AF XY: 0.0497 AC XY: 36167 AN XY: 727054

African (AFR) AF: 0.00797 AC: 267 AN: 33480

American (AMR) AF: 0.0222 AC: 991 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 1105 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0315 AC: 2714 AN: 86258

European-Finnish (FIN) AF: 0.0316 AC: 1679 AN: 53074

Middle Eastern (MID) AF: 0.0390 AC: 225 AN: 5768

European-Non Finnish (NFE) AF: 0.0570 AC: 63405 AN: 1111956

Other (OTH) AF: 0.0459 AC: 2773 AN: 60390

GnomAD4 genome AF: 0.0339 AC: 5169 AN: 152312 Hom.: 103 Cov.: 32 AF XY: 0.0318 AC XY: 2366 AN XY: 74468

African (AFR) AF: 0.00998 AC: 415 AN: 41576

American (AMR) AF: 0.0278 AC: 426 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0246 AC: 119 AN: 4828

European-Finnish (FIN) AF: 0.0304 AC: 323 AN: 10620

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0530 AC: 3607 AN: 68022

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0472 Hom.: 434

Bravo AF: 0.0321

TwinsUK AF: 0.0558 AC: 207

ALSPAC AF: 0.0610 AC: 235

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0555 AC: 477

ExAC AF: 0.0345 AC: 4188

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0555

EpiControl AF: 0.0490

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	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	Benign	0.085
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.096
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.027
Sift	Benign	0.12	T
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.058
MPC		0.38
ClinPred		0.0035	T
GERP RS		2.4
Varity_R		0.037
gMVP		0.33
Mutation Taster		=96/4	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: rs35280470; hg19: chr7-42004664;