chr12-57471538-G-A

Position:

chr12-57471538-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.925

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
GLI1	NM_005269.3 linkuse as main transcript	c.2798G>A	p.Gly933Asp	missense_variant	12/12	ENST00000228682.7	NP_005260.1	P08151-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GLI1	ENST00000228682.7 linkuse as main transcript	c.2798G>A	p.Gly933Asp	missense_variant	12/12	1	NM_005269.3	ENSP00000228682.2	P08151-1
GLI1	ENST00000528467.1 linkuse as main transcript	c.2675G>A	p.Gly892Asp	missense_variant	10/10	1		ENSP00000434408.1	P08151-2
GLI1	ENST00000546141.5 linkuse as main transcript	c.2675G>A	p.Gly892Asp	missense_variant	11/11	5		ENSP00000441006.1	P08151-2
GLI1	ENST00000543426.5 linkuse as main transcript	c.2414G>A	p.Gly805Asp	missense_variant	10/10	5		ENSP00000437607.1	P08151-3

Frequencies

GnomAD3 genomes

AF:

0.477

AC:

72391

AN:

151750

Hom.:

19480

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.585

AC XY:

424615

AN XY:

726372

show subpopulations

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.:

AF XY:

0.470

AC XY:

34860

AN XY:

74214

show subpopulations

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 21085059) -

GLI1-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

Polydactyly, postaxial, type A8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Polydactyly of a biphalangeal thumb

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.30

.;T;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.60

T;T;T;.

MetaRNN

Benign

0.000061

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;N;.;.

PrimateAI

Benign

0.38

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over