rs146458902

Variant names:

• chr7-42148252-C-T
• rs146458902
• NM_000168.6:c.341G>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.341G>A​(p.Arg114Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,612,252 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (17 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.54
• Publications: 10 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=0.014516115).
• BP6: Variant 7-42148252-C-T is Benign according to our data. Variant chr7-42148252-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360260.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 = 0.00261 (397/152084) while in subpopulation NFE AF = 0.00444 (302/67982). AF 95% confidence interval is 0.00403. There are 1 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.341G>A	p.Arg114Lys	missense	Exon 3 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.341G>A	p.Arg114Lys	missense	Exon 3 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.341G>A	p.Arg114Lys	missense	Exon 3 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.341G>A	p.Arg114Lys	missense	Exon 3 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 151966 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00242 AC: 595 AN: 245988 AF XY: 0.00243

Gnomad AFR exome AF: 0.000764

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00393

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.000796

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00445 AC: 6498 AN: 1460168 Hom.: 17 Cov.: 34 AF XY: 0.00432 AC XY: 3136 AN XY: 726200

African (AFR) AF: 0.000717 AC: 24 AN: 33456

American (AMR) AF: 0.000516 AC: 23 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00530 AC: 138 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000815 AC: 7 AN: 85892

European-Finnish (FIN) AF: 0.00120 AC: 64 AN: 53316

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00543 AC: 6028 AN: 1111136

Other (OTH) AF: 0.00351 AC: 212 AN: 60344

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152084 Hom.: 1 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74338

African (AFR) AF: 0.000964 AC: 40 AN: 41502

American (AMR) AF: 0.00124 AC: 19 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00444 AC: 302 AN: 67982

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00408 Hom.: 6

Bravo AF: 0.00257

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Greig cephalopolysyndactyly syndrome (2)
-	-	1	GLI3-related disorder (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
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.70	N
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		0.99	D
Vest4		0.68
MVP		0.78
MPC		0.61
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.48
gMVP		0.48
Mutation Taster		=64/36	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: rs146458902; hg19: chr7-42187851; COSMIC: COSV106114095;