Genetic Variant GLI1:c.-28+299T>G (chr12-57460500-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005269.3(GLI1):c.-28+299T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 152,402 control chromosomes in the GnomAD database, including 32,340 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 32267 hom., cov: 31)

Exomes 𝑓: 0.61 ( 73 hom. )

Consequence

GLI1
NM_005269.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

Publications

7 publications found

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 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)

GLI1 links:

ENSG00000287200 (HGNC:):

ENSG00000287200 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3 link	c.-28+299T>G		intron_variant	Intron 1 of 11	ENST00000228682.7	NP_005260.1	P08151-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI1	ENST00000228682.7 link	c.-28+299T>G		intron_variant	Intron 1 of 11	1	NM_005269.3	ENSP00000228682.2		P08151-1

Frequencies

GnomAD3 genomes

AF:

0.646

AC:

98108

AN:

151880

Hom.:

32240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.677

Gnomad AMI

AF:

0.746

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.722

Gnomad EAS

AF:

0.394

Gnomad SAS

AF:

0.516

Gnomad FIN

AF:

0.571

Gnomad MID

AF:

0.823

Gnomad NFE

AF:

0.685

Gnomad OTH

AF:

0.665

GnomAD4 exome

AF:

0.611

AC:

247

AN:

404

Hom.:

Cov.:

AF XY:

0.640

AC XY:

137

AN XY:

214

show subpopulations

African (AFR)

AF:

0.667

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.613

AC:

190

AN:

310

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.600

AC:

AN:

Other (OTH)

AF:

0.700

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.646

AC:

98173

AN:

151998

Hom.:

32267

Cov.:

AF XY:

0.635

AC XY:

47144

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.678

AC:

28088

AN:

41440

American (AMR)

AF:

0.535

AC:

8160

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.722

AC:

2503

AN:

3468

East Asian (EAS)

AF:

0.394

AC:

2029

AN:

5156

South Asian (SAS)

AF:

0.516

AC:

2485

AN:

4820

European-Finnish (FIN)

AF:

0.571

AC:

6043

AN:

10574

Middle Eastern (MID)

AF:

0.806

AC:

237

AN:

294

European-Non Finnish (NFE)

AF:

0.685

AC:

46552

AN:

67966

Other (OTH)

AF:

0.662

AC:

1396

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1749

3498

5247

6996

8745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.670

Hom.:

12114

Bravo

AF:

0.641

Asia WGS

AF:

0.500

AC:

1740

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.52

PhyloP100

1.1

PromoterAI

0.043

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-57460500-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over