rs2228224

chr12-57471538-G-Achr12-57471538-G-Cchr12-57471538-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005269.3(GLI1):c.2798G>A(p.Gly933Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,611,922 control chromosomes in the GnomAD database, including 278,661 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (19475 hom., cov: 30)
  • Exomes 𝑓: 0.59 (259186 hom.)
• Consequence: GLI1 NM_005269.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.925

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=6.1342624E-5).
• BP6: Variant 12-57471538-G-A is Benign according to our data. Variant chr12-57471538-G-A is described in ClinVar as [Benign]. Clinvar id is 1240928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI1	NM_005269.3	c.2798G>A	p.Gly933Asp	missense_variant	12/12	ENST00000228682.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI1	ENST00000228682.7	c.2798G>A	p.Gly933Asp	missense_variant	12/12	1	NM_005269.3	P1
GLI1	ENST00000528467.1	c.2675G>A	p.Gly892Asp	missense_variant	10/10	1
GLI1	ENST00000546141.5	c.2675G>A	p.Gly892Asp	missense_variant	11/11	5
GLI1	ENST00000543426.5	c.2414G>A	p.Gly805Asp	missense_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72391 AN: 151750 Hom.: 19480 Cov.: 30

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.526

GnomAD3 exomes AF: 0.497 AC: 124185 AN: 249686 Hom.: 33817 AF XY: 0.511 AC XY: 69041 AN XY: 135090

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.605

Gnomad EAS exome AF: 0.292

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.561

GnomAD4 exome AF: 0.586 AC: 856294 AN: 1460054 Hom.: 259186 Cov.: 44 AF XY: 0.585 AC XY: 424615 AN XY: 726372

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.400

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.631

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.477 AC: 72396 AN: 151868 Hom.: 19475 Cov.: 30 AF XY: 0.470 AC XY: 34860 AN XY: 74214

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.610

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.517

Gnomad4 NFE AF: 0.630

Gnomad4 OTH AF: 0.520

Alfa AF: 0.599 Hom.: 55931

Bravo AF: 0.456

TwinsUK AF: 0.632 AC: 2345

ALSPAC AF: 0.636 AC: 2450

ESP6500AA AF: 0.244 AC: 1073

ESP6500EA AF: 0.629 AC: 5406

ExAC AF: 0.500 AC: 60752

Asia WGS AF: 0.359 AC: 1249 AN: 3478

EpiCase AF: 0.639

EpiControl AF: 0.641

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polydactyly, postaxial, type A8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

GLI1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2020

This variant is associated with the following publications: (PMID: 21085059) -

Preaxial hand polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.60	T;T;T;.
MetaRNN	Benign	0.000061	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.53	N;N;N;N
REVEL	Benign	0.060
Sift	Uncertain	0.028	D;T;T;T
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.10	.;B;.;.
Vest4		0.063
MPC		0.23
ClinPred		0.011	T
GERP RS		0.56
Varity_R		0.083
gMVP		0.45

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: rs2228224; hg19: chr12-57865321; COSMIC: COSV57357796; COSMIC: COSV57357796;