rs2228224

Variant names:

• chr12-57471538-G-A
• rs2228224
• NM_005269.3:c.2798G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57471538-G-A
• chr12-57471538-G-C
• chr12-57471538-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:5
• Conservation: PhyloP100: 0.925
• Publications: 62 publications found

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 Gene-Disease associations (from GenCC):

• Ellis-van Creveld syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• polydactyly of a biphalangeal thumb

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• polydactyly, postaxial, type A8

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GLI1	NM_005269.3	c.2798G>A	p.Gly933Asp	missense_variant	Exon 12 of 12	ENST00000228682.7	NP_005260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7	c.2798G>A	p.Gly933Asp	missense_variant	Exon 12 of 12	1	NM_005269.3	ENSP00000228682.2
GLI1	ENST00000528467.1	c.2675G>A	p.Gly892Asp	missense_variant	Exon 10 of 10	1		ENSP00000434408.1
GLI1	ENST00000546141.5	c.2675G>A	p.Gly892Asp	missense_variant	Exon 11 of 11	5		ENSP00000441006.1
GLI1	ENST00000543426.5	c.2414G>A	p.Gly805Asp	missense_variant	Exon 10 of 10	5		ENSP00000437607.1

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

GnomAD2 exomes AF: 0.497 AC: 124185 AN: 249686 AF XY: 0.511

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 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

African (AFR) AF: 0.228 AC: 7620 AN: 33434

American (AMR) AF: 0.336 AC: 14958 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 15726 AN: 26062

East Asian (EAS) AF: 0.400 AC: 15882 AN: 39696

South Asian (SAS) AF: 0.432 AC: 37224 AN: 86170

European-Finnish (FIN) AF: 0.515 AC: 27356 AN: 53080

Middle Eastern (MID) AF: 0.650 AC: 3745 AN: 5762

European-Non Finnish (NFE) AF: 0.631 AC: 700578 AN: 1111024

Other (OTH) AF: 0.550 AC: 33205 AN: 60324

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

African (AFR) AF: 0.241 AC: 9962 AN: 41402

American (AMR) AF: 0.435 AC: 6640 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2113 AN: 3466

East Asian (EAS) AF: 0.323 AC: 1660 AN: 5138

South Asian (SAS) AF: 0.427 AC: 2056 AN: 4816

European-Finnish (FIN) AF: 0.517 AC: 5442 AN: 10536

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.630 AC: 42780 AN: 67926

Other (OTH) AF: 0.520 AC: 1099 AN: 2112

Alfa AF: 0.576 Hom.: 85474

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

Submissions by phenotype

not provided Benign:2

Feb 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

GLI1-related disorder Benign:1

Aug 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polydactyly of a biphalangeal thumb Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.30	.;T;.;.
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
MutationAssessor	Benign	0.55	.;N;.;.
PhyloP100		0.93
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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