GeneBe

rs35961850

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000168.6(GLI3):​c.900C>T​(p.Ser300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0864 in 1,613,370 control chromosomes in the GnomAD database, including 6,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 536 hom., cov: 33)
Exomes 𝑓: 0.088 ( 6398 hom. )

Consequence

GLI3
NM_000168.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.809
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 7-42040166-G-A is Benign according to our data. Variant chr7-42040166-G-A is described in ClinVar as [Benign]. Clinvar id is 255451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-42040166-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.809 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLI3NM_000168.6 linkuse as main transcriptc.900C>T p.Ser300= synonymous_variant 7/15 ENST00000395925.8 NP_000159.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLI3ENST00000395925.8 linkuse as main transcriptc.900C>T p.Ser300= synonymous_variant 7/155 NM_000168.6 ENSP00000379258 P1

Frequencies

GnomAD3 genomes
AF:
0.0740
AC:
11249
AN:
152094
Hom.:
536
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0348
Gnomad AMI
AF:
0.133
Gnomad AMR
AF:
0.0578
Gnomad ASJ
AF:
0.0557
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.0217
Gnomad FIN
AF:
0.117
Gnomad MID
AF:
0.0637
Gnomad NFE
AF:
0.105
Gnomad OTH
AF:
0.0564
GnomAD3 exomes
AF:
0.0693
AC:
17414
AN:
251442
Hom.:
800
AF XY:
0.0704
AC XY:
9564
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.0342
Gnomad AMR exome
AF:
0.0348
Gnomad ASJ exome
AF:
0.0593
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.0282
Gnomad FIN exome
AF:
0.117
Gnomad NFE exome
AF:
0.0989
Gnomad OTH exome
AF:
0.0663
GnomAD4 exome
AF:
0.0877
AC:
128178
AN:
1461158
Hom.:
6398
Cov.:
32
AF XY:
0.0864
AC XY:
62843
AN XY:
726952
show subpopulations
Gnomad4 AFR exome
AF:
0.0338
Gnomad4 AMR exome
AF:
0.0371
Gnomad4 ASJ exome
AF:
0.0602
Gnomad4 EAS exome
AF:
0.000252
Gnomad4 SAS exome
AF:
0.0277
Gnomad4 FIN exome
AF:
0.120
Gnomad4 NFE exome
AF:
0.0992
Gnomad4 OTH exome
AF:
0.0750
GnomAD4 genome
AF:
0.0739
AC:
11256
AN:
152212
Hom.:
536
Cov.:
33
AF XY:
0.0731
AC XY:
5444
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.0349
Gnomad4 AMR
AF:
0.0578
Gnomad4 ASJ
AF:
0.0557
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.0213
Gnomad4 FIN
AF:
0.117
Gnomad4 NFE
AF:
0.105
Gnomad4 OTH
AF:
0.0577
Alfa
AF:
0.0923
Hom.:
407
Bravo
AF:
0.0642
Asia WGS
AF:
0.0220
AC:
79
AN:
3478
EpiCase
AF:
0.0913
EpiControl
AF:
0.0861

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Greig cephalopolysyndactyly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Pallister-Hall syndrome;C0265306:Greig cephalopolysyndactyly syndrome;C1868111:Polysyndactyly 4;C4282400:Polydactyly, postaxial, type A1 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 02, 2022- -
Pallister-Hall syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Polydactyly Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
3.3
DANN
Benign
0.75

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

LitVar

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

Other links and lift over

dbSNP: rs35961850; hg19: chr7-42079765; COSMIC: COSV67885640; API