7-41961326-C-T

Variant names:

Variant summary

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

The NM_000168.6(GLI3):c.*3004G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,342 control chromosomes in the GnomAD database, including 7,217 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 0.28 ( 7200 hom., cov: 33)

Exomes 𝑓: 0.34 ( 17 hom. )

Consequence

GLI3
NM_000168.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.637

Publications

16 publications found

Variant links:

Genes affected

GLI3 (HGNC:4319): (GLI family zinc finger 3) This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

GLI3 Gene-Disease associations (from GenCC):

Greig cephalopolysyndactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
Pallister-Hall syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics, Orphanet
polydactyly, postaxial, type A1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
polysyndactyly 4
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
tibial hemimelia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
acrocallosal syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GLI3 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=-0.56).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI3	NM_000168.6 link	c.*3004G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000395925.8	NP_000159.3	P10071

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLI3	ENST00000395925.8 link	c.*3004G>A	3_prime_UTR_variant	Exon 15 of 15	5	NM_000168.6	ENSP00000379258.3	P10071
GLI3	ENST00000677605.1 link	c.*3004G>A	3_prime_UTR_variant	Exon 15 of 15			ENSP00000503743.1	P10071
GLI3	ENST00000678429.1 link	c.*3004G>A	3_prime_UTR_variant	Exon 15 of 15			ENSP00000502957.1	P10071
GLI3	ENST00000677288.1 link	c.*3004G>A	3_prime_UTR_variant	Exon 14 of 14			ENSP00000503986.1	A0A7I2V4X9

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42207

AN:

151894

Hom.:

7194

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0829

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.354

Gnomad EAS

AF:

0.589

Gnomad SAS

AF:

0.345

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.290

GnomAD4 exome

AF:

0.342

AC:

113

AN:

330

Hom.:

Cov.:

AF XY:

0.328

AC XY:

AN XY:

204

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.343

AC:

109

AN:

318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.375

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

42237

AN:

152012

Hom.:

7200

Cov.:

AF XY:

0.282

AC XY:

20917

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0829

AC:

3440

AN:

41510

American (AMR)

AF:

0.343

AC:

5242

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

1225

AN:

3464

East Asian (EAS)

AF:

0.588

AC:

3034

AN:

5156

South Asian (SAS)

AF:

0.348

AC:

1674

AN:

4816

European-Finnish (FIN)

AF:

0.336

AC:

3541

AN:

10550

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.341

AC:

23145

AN:

67922

Other (OTH)

AF:

0.298

AC:

628

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1436

2872

4307

5743

7179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.310

Hom.:

16881

Bravo

AF:

0.270

Asia WGS

AF:

0.452

AC:

1572

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Greig cephalopolysyndactyly syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pallister-Hall syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Polydactyly

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.8

(source)

DANN

Benign

0.66

PhyloP100

0.64

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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7-41961326-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over