12-57465251-G-A

Position:

• chr12-57465251-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005269.3(GLI1):​c.530G>A​(p.Cys177Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLI1 NM_005269.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.71

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28502858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI1	NM_005269.3	c.530G>A	p.Cys177Tyr	missense_variant	5/12	ENST00000228682.7	NP_005260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7	c.530G>A	p.Cys177Tyr	missense_variant	5/12	1	NM_005269.3	ENSP00000228682.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.77	.;.;D;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T;T;T;T;.
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.0	.;.;L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N;N;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Benign	0.16	T;T;D;D;D
Polyphen		0.0010	.;.;B;.;.
Vest4		0.58, 0.59, 0.53
MutPred		0.41		.;.;Gain of catalytic residue at G172 (P = 0.01);.;.;
MVP		0.77
MPC		0.80
ClinPred		0.80	D
GERP RS		2.7
Varity_R		0.34
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs193921005; hg19: chr12-57859034; COSMIC: COSV57359589; COSMIC: COSV57359589;