7-41972378-C-T

Variant names:

• chr7-41972378-C-T
• rs116840747
• NM_000168.6:c.2062G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000168.6(GLI3):​c.2062G>A​(p.Glu688Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLI3 NM_000168.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.15
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38929564).

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.2062G>A	p.Glu688Lys	missense	Exon 13 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.2062G>A	p.Glu688Lys	missense	Exon 13 of 15	ENSP00000379258.3	P10071
	GLI3	ENST00000677605.1		c.2062G>A	p.Glu688Lys	missense	Exon 13 of 15	ENSP00000503743.1	P10071
	GLI3	ENST00000678429.1		c.2062G>A	p.Glu688Lys	missense	Exon 13 of 15	ENSP00000502957.1	P10071

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.88	P
Vest4		0.88
MutPred		0.33		Gain of methylation at E688 (P = 0.0019)
MVP		0.73
MPC		1.0
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.59
gMVP		0.53
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs116840747; hg19: chr7-42011977;