NM_005269.3:c.786C>A

Variant names:

• chr12-57466263-C-A
• rs7973381
• NM_005269.3:c.786C>A

Variant summary

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

The NM_005269.3(GLI1):​c.786C>A​(p.His262Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,274 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H262H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLI1 NM_005269.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 20 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI1	NM_005269.3	MANE Select	c.786C>A	p.His262Gln	missense	Exon 8 of 12	NP_005260.1	P08151-1
	GLI1	NM_001167609.2		c.663C>A	p.His221Gln	missense	Exon 7 of 11	NP_001161081.1	P08151-2
	GLI1	NM_001160045.2		c.402C>A	p.His134Gln	missense	Exon 6 of 10	NP_001153517.1	P08151-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI1	ENST00000228682.7	TSL:1 MANE Select	c.786C>A	p.His262Gln	missense	Exon 8 of 12	ENSP00000228682.2	P08151-1
	GLI1	ENST00000528467.1	TSL:1	c.663C>A	p.His221Gln	missense	Exon 6 of 10	ENSP00000434408.1	P08151-2
	GLI1	ENST00000546141.5	TSL:5	c.663C>A	p.His221Gln	missense	Exon 7 of 11	ENSP00000441006.1	P08151-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461274 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726940

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111676

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 625

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	2.5
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.54
Sift	Benign	0.15	T
Sift4G	Uncertain	0.060	T
Polyphen		0.13	B
Vest4		0.57
MutPred		0.48		Gain of catalytic residue at E267 (P = 0.0101)
MVP		0.56
MPC		0.69
ClinPred		0.88	D
GERP RS		-8.1
Varity_R		0.45
gMVP		0.44
Mutation Taster		=20/80	disease causing

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: rs7973381; hg19: chr12-57860046;