7-41967848-C-T

Variant names:

• chr7-41967848-C-T
• rs121917710
• NM_000168.6:c.2179G>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.2179G>A​(p.Gly727Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00635 in 1,614,096 control chromosomes in the GnomAD database, including 53 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. G727G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (51 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 5.65
• Publications: 34 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 (MetaRNN=0.008583009).
• BP6: Variant 7-41967848-C-T is Benign according to our data. Variant chr7-41967848-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13821.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 = 0.00506 (771/152228) while in subpopulation NFE AF = 0.00819 (557/68018). AF 95% confidence interval is 0.00763. There are 2 homozygotes in GnomAd4. There are 382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2179G>A	p.Gly727Arg	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.2179G>A	p.Gly727Arg	missense	Exon 14 of 15	ENSP00000379258.3
	GLI3	ENST00000677605.1		c.2179G>A	p.Gly727Arg	missense	Exon 14 of 15	ENSP00000503743.1
	GLI3	ENST00000678429.1		c.2179G>A	p.Gly727Arg	missense	Exon 14 of 15	ENSP00000502957.1

Frequencies

GnomAD3 genomes AF: 0.00508 AC: 772 AN: 152110 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00820

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00527 AC: 1325 AN: 251488 AF XY: 0.00556

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00762

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00649 AC: 9484 AN: 1461868 Hom.: 51 Cov.: 32 AF XY: 0.00660 AC XY: 4797 AN XY: 727240

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00579 AC: 499 AN: 86256

European-Finnish (FIN) AF: 0.00766 AC: 409 AN: 53420

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.00722 AC: 8033 AN: 1111988

Other (OTH) AF: 0.00528 AC: 319 AN: 60396

GnomAD4 genome AF: 0.00506 AC: 771 AN: 152228 Hom.: 2 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74418

African (AFR) AF: 0.000722 AC: 30 AN: 41536

American (AMR) AF: 0.00190 AC: 29 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00819 AC: 557 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00634 Hom.: 13

Bravo AF: 0.00392

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00571 AC: 693

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00735

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Greig cephalopolysyndactyly syndrome (1)
-	-	1	Pallister-Hall syndrome (1)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)
-	-	1	Polydactyly (1)
-	-	1	Postaxial polydactyly (1)
-	1	-	Postaxial polydactyly, type A1/B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.013	D
Sift4G	Benign	0.092	T
Polyphen		0.99	D
Vest4		0.94
MutPred		0.79		Loss of glycosylation at S726 (P = 0.0404)
MVP		0.87
MPC		1.1
ClinPred		0.036	T
GERP RS		5.8
Varity_R		0.68
gMVP		0.56
Mutation Taster		=88/12	disease causing (ClinVar)

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: rs121917710; hg19: chr7-42007446; COSMIC: COSV67887449; COSMIC: COSV67887449;