chr12-57465224-C-G

Position:

• chr12-57465224-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005269.3(GLI1):​c.503C>G​(p.Pro168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000816 in 1,613,506 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (25 hom.)
• Consequence: GLI1 NM_005269.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.05

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005177796).
• BP6: Variant 12-57465224-C-G is Benign according to our data. Variant chr12-57465224-C-G is described in ClinVar as [Benign]. Clinvar id is 730133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000374 (57/152338) while in subpopulation SAS AF= 0.011 (53/4828). AF 95% confidence interval is 0.00862. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI1	NM_005269.3	c.503C>G	p.Pro168Arg	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.503C>G	p.Pro168Arg	missense_variant	5/12	1	NM_005269.3	ENSP00000228682.2

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00172 AC: 428 AN: 248996 Hom.: 6 AF XY: 0.00228 AC XY: 307 AN XY: 134744

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000987

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000862 AC: 1259 AN: 1461168 Hom.: 25 Cov.: 33 AF XY: 0.00127 AC XY: 925 AN XY: 726896

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GLI1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2017	- -

GLI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	.;.;D;.;.
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.72	T;T;T;T;.
MetaRNN	Benign	0.0052	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	.;.;L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.037
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Benign	0.11	T;D;D;D;D
Polyphen		0.94	.;.;P;.;.
Vest4		0.42, 0.41, 0.49
MutPred		0.35		.;.;Gain of catalytic residue at I165 (P = 0.0018);.;.;
MVP		0.82
MPC		0.54
ClinPred		0.026	T
GERP RS		2.7
Varity_R		0.049
gMVP		0.28

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: rs542007910; hg19: chr12-57859007; COSMIC: COSV57364769; COSMIC: COSV57364769;