12-57465648-G-T

Variant names:

• chr12-57465648-G-T
• rs2228225
• NM_005269.3:c.576G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005269.3(GLI1):​c.576G>T​(p.Glu192Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E192E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLI1 NM_005269.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• Publications: 30 publications found

Genes affected

GLI1 (HGNC:4317): (GLI family zinc finger 1) This gene encodes a member of the Kruppel family of zinc finger proteins. The encoded transcription factor is activated by the sonic hedgehog signal transduction cascade and regulates stem cell proliferation. The activity and nuclear localization of this protein is negatively regulated by p53 in an inhibitory loop. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

GLI1 Gene-Disease associations (from GenCC):

• Ellis-van Creveld syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• polydactyly of a biphalangeal thumb

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• polydactyly, postaxial, type A8

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005269.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI1	NM_005269.3	MANE Select	c.576G>T	p.Glu192Asp	missense	Exon 6 of 12	NP_005260.1
	GLI1	NM_001167609.2		c.453G>T	p.Glu151Asp	missense	Exon 5 of 11	NP_001161081.1
	GLI1	NM_001160045.2		c.192G>T	p.Glu64Asp	missense	Exon 4 of 10	NP_001153517.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI1	ENST00000228682.7	TSL:1 MANE Select	c.576G>T	p.Glu192Asp	missense	Exon 6 of 12	ENSP00000228682.2
	GLI1	ENST00000528467.1	TSL:1	c.453G>T	p.Glu151Asp	missense	Exon 4 of 10	ENSP00000434408.1
	GLI1	ENST00000546141.5	TSL:5	c.453G>T	p.Glu151Asp	missense	Exon 5 of 11	ENSP00000441006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.074
Sift	Uncertain	0.029	D
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.30		Gain of helix (P = 0.132)
MVP		0.73
MPC		0.64
ClinPred		0.55	D
GERP RS		1.3
Varity_R		0.071
gMVP		0.15
Mutation Taster		=92/8	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: rs2228225; hg19: chr12-57859431;