rs929387

Variant names:

• chr7-41966080-G-A
• rs929387
• NM_000168.6:c.2993C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-41966080-G-A
• chr7-41966080-G-C

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.2993C>T​(p.Pro998Leu) variant causes a missense change. The variant allele was found at a frequency of 0.346 in 1,567,904 control chromosomes in the GnomAD database, including 102,269 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P998A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (9226 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93043 hom.)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.99
• Publications: 45 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=1.0673986E-6).
• BP6: Variant 7-41966080-G-A is Benign according to our data. Variant chr7-41966080-G-A is described in ClinVar as Benign. ClinVar VariationId is 255433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 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.2993C>T	p.Pro998Leu	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.2993C>T	p.Pro998Leu	missense	Exon 15 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.2993C>T	p.Pro998Leu	missense	Exon 15 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.2993C>T	p.Pro998Leu	missense	Exon 15 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49128 AN: 151778 Hom.: 9209 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.341

GnomAD2 exomes AF: 0.425 AC: 74159 AN: 174410 AF XY: 0.420

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.569

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.788

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.348 AC: 493056 AN: 1416008 Hom.: 93043 Cov.: 40 AF XY: 0.351 AC XY: 246594 AN XY: 701882

African (AFR) AF: 0.189 AC: 6165 AN: 32616

American (AMR) AF: 0.551 AC: 22203 AN: 40312

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 10023 AN: 25340

East Asian (EAS) AF: 0.819 AC: 30855 AN: 37696

South Asian (SAS) AF: 0.465 AC: 38482 AN: 82838

European-Finnish (FIN) AF: 0.326 AC: 12281 AN: 37716

Middle Eastern (MID) AF: 0.362 AC: 1984 AN: 5488

European-Non Finnish (NFE) AF: 0.319 AC: 349665 AN: 1095124

Other (OTH) AF: 0.363 AC: 21398 AN: 58878

GnomAD4 genome AF: 0.324 AC: 49176 AN: 151896 Hom.: 9226 Cov.: 32 AF XY: 0.331 AC XY: 24603 AN XY: 74224

African (AFR) AF: 0.189 AC: 7837 AN: 41500

American (AMR) AF: 0.440 AC: 6723 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4072 AN: 5060

South Asian (SAS) AF: 0.492 AC: 2371 AN: 4816

European-Finnish (FIN) AF: 0.336 AC: 3549 AN: 10572

Middle Eastern (MID) AF: 0.315 AC: 90 AN: 286

European-Non Finnish (NFE) AF: 0.324 AC: 21995 AN: 67880

Other (OTH) AF: 0.347 AC: 734 AN: 2114

Alfa AF: 0.329 Hom.: 5735

Bravo AF: 0.330

TwinsUK AF: 0.304 AC: 1128

ALSPAC AF: 0.313 AC: 1208

ESP6500AA AF: 0.181 AC: 654

ESP6500EA AF: 0.293 AC: 2170

ExAC AF: 0.368 AC: 40613

Asia WGS AF: 0.624 AC: 2167 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Greig cephalopolysyndactyly syndrome (2)
-	-	2	not provided (2)
-	-	2	Pallister-Hall syndrome (2)
-	-	1	Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome (1)
-	-	1	Polydactyly (1)
-	-	1	Polydactyly, postaxial, type A1 (1)
-	-	1	Polysyndactyly 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.68
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.45	N
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.16
Sift	Benign	0.42	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.023
MPC		0.30
ClinPred		0.042	T
GERP RS		3.8
Varity_R		0.054
gMVP		0.30
Mutation Taster		=99/1	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: rs929387; hg19: chr7-42005678; COSMIC: COSV67884831;