rs62622373

Variant names:

• chr7-41967603-T-C
• rs62622373
• NM_000168.6:c.2424A>G

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.2424A>G​(p.Ile808Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,611,074 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I808K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (12 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.34
• Publications: 13 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=0.009604782).
• BP6: Variant 7-41967603-T-C is Benign according to our data. Variant chr7-41967603-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235210.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 = 0.00189 (287/152246) while in subpopulation NFE AF = 0.0029 (197/68012). AF 95% confidence interval is 0.00257. There are 0 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.2424A>G	p.Ile808Met	missense	Exon 14 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.2424A>G	p.Ile808Met	missense	Exon 14 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.2424A>G	p.Ile808Met	missense	Exon 14 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.2424A>G	p.Ile808Met	missense	Exon 14 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00204 AC: 512 AN: 250992 AF XY: 0.00217

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00233 AC: 3394 AN: 1458828 Hom.: 12 Cov.: 31 AF XY: 0.00222 AC XY: 1608 AN XY: 725890

African (AFR) AF: 0.000390 AC: 13 AN: 33370

American (AMR) AF: 0.00226 AC: 101 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 262 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86196

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53418

Middle Eastern (MID) AF: 0.00351 AC: 19 AN: 5414

European-Non Finnish (NFE) AF: 0.00251 AC: 2787 AN: 1109708

Other (OTH) AF: 0.00302 AC: 182 AN: 60262

GnomAD4 genome AF: 0.00189 AC: 287 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74432

African (AFR) AF: 0.000217 AC: 9 AN: 41548

American (AMR) AF: 0.00203 AC: 31 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68012

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00248 Hom.: 6

Bravo AF: 0.00193

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Greig cephalopolysyndactyly syndrome (3)
-	-	2	not specified (2)
-	-	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	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.63
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.75
MVP		0.88
MPC		0.31
ClinPred		0.021	T
GERP RS		4.2
Varity_R		0.088
gMVP		0.29
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62622373; hg19: chr7-42007201; COSMIC: COSV67886500;