dbSNP rs3817474: GLI1:c.390-59G>A (chr12-57465052-G-A) – 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.390-59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 1,550,560 control chromosomes in the GnomAD database, including 266,910 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 0.48 ( 19418 hom., cov: 33)

Exomes 𝑓: 0.59 ( 247492 hom. )

Consequence

GLI1
NM_005269.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.851

Publications

11 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:

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=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI1	NM_005269.3 link	c.390-59G>A		intron_variant	Intron 4 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.390-59G>A		intron_variant	Intron 4 of 11	1	NM_005269.3	ENSP00000228682.2		P08151-1

Frequencies

GnomAD3 genomes

AF:

0.475

AC:

72286

AN:

152024

Hom.:

19423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.488

Gnomad AMR

AF:

0.436

Gnomad ASJ

AF:

0.579

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.427

Gnomad FIN

AF:

0.518

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.629

Gnomad OTH

AF:

0.525

GnomAD4 exome

AF:

0.585

AC:

818085

AN:

1398418

Hom.:

247492

Cov.:

AF XY:

0.583

AC XY:

407805

AN XY:

699396

show subpopulations

African (AFR)

AF:

0.225

AC:

7246

AN:

32200

American (AMR)

AF:

0.336

AC:

15009

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

14917

AN:

25754

East Asian (EAS)

AF:

0.401

AC:

15778

AN:

39388

South Asian (SAS)

AF:

0.432

AC:

36747

AN:

85002

European-Finnish (FIN)

AF:

0.516

AC:

27490

AN:

53326

Middle Eastern (MID)

AF:

0.651

AC:

3673

AN:

5640

European-Non Finnish (NFE)

AF:

0.631

AC:

665283

AN:

1054200

Other (OTH)

AF:

0.548

AC:

31942

AN:

58262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

17246

34492

51737

68983

86229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.475

AC:

72291

AN:

152142

Hom.:

19418

Cov.:

AF XY:

0.468

AC XY:

34827

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.238

AC:

9864

AN:

41490

American (AMR)

AF:

0.435

AC:

6653

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

2012

AN:

3472

East Asian (EAS)

AF:

0.325

AC:

1678

AN:

5162

South Asian (SAS)

AF:

0.428

AC:

2067

AN:

4834

European-Finnish (FIN)

AF:

0.518

AC:

5471

AN:

10564

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.629

AC:

42803

AN:

68002

Other (OTH)

AF:

0.519

AC:

1098

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1761

3522

5284

7045

8806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.509

Hom.:

3181

Bravo

AF:

0.454

Asia WGS

AF:

0.359

AC:

1252

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.8

(source)

DANN

Benign

0.62

PhyloP100

0.85

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs3817474

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