rs7973381

chr12-57466263-C-Achr12-57466263-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI1	NM_005269.3	c.786C>A	p.His262Gln	missense_variant	8/12	ENST00000228682.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI1	ENST00000228682.7	c.786C>A	p.His262Gln	missense_variant	8/12	1	NM_005269.3	P1

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.96	D;D;D;D;.
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.000040	P;P;P
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.9	D;D;D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.15	T;T;T;D;D
Sift4G	Uncertain	0.060	T;D;D;D;D
Polyphen		0.13	.;.;B;.;.
Vest4		0.57, 0.83, 0.85
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7973381; hg19: chr12-57860046;