GeneBe

rs79049330

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000168.6(GLI3):​c.3083G>T​(p.Ser1028Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,604,554 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1028S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 32)
Exomes 𝑓: 0.019 ( 328 hom. )

Consequence

GLI3
NM_000168.6 missense

Scores

6
12

Clinical Significance

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

Conservation

PhyloP100: 3.31
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0055089593).
BP6
Variant 7-41965990-C-A is Benign according to our data. Variant chr7-41965990-C-A is described in ClinVar as [Benign]. Clinvar id is 137485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-41965990-C-A is described in Lovd as [Benign]. Variant chr7-41965990-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1906/152264) while in subpopulation NFE AF= 0.0214 (1455/67990). AF 95% confidence interval is 0.0205. There are 21 homozygotes in gnomad4. There are 789 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1906 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLI3NM_000168.6 linkuse as main transcriptc.3083G>T p.Ser1028Ile missense_variant 15/15 ENST00000395925.8 NP_000159.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLI3ENST00000395925.8 linkuse as main transcriptc.3083G>T p.Ser1028Ile missense_variant 15/155 NM_000168.6 ENSP00000379258 P1

Frequencies

GnomAD3 genomes
AF:
0.0125
AC:
1908
AN:
152146
Hom.:
21
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00466
Gnomad AMI
AF:
0.00768
Gnomad AMR
AF:
0.00916
Gnomad ASJ
AF:
0.00807
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00451
Gnomad MID
AF:
0.00637
Gnomad NFE
AF:
0.0214
Gnomad OTH
AF:
0.0134
GnomAD3 exomes
AF:
0.0124
AC:
2906
AN:
234352
Hom.:
30
AF XY:
0.0123
AC XY:
1581
AN XY:
128670
show subpopulations
Gnomad AFR exome
AF:
0.00438
Gnomad AMR exome
AF:
0.00655
Gnomad ASJ exome
AF:
0.00859
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00191
Gnomad FIN exome
AF:
0.00671
Gnomad NFE exome
AF:
0.0218
Gnomad OTH exome
AF:
0.0106
GnomAD4 exome
AF:
0.0193
AC:
28016
AN:
1452290
Hom.:
328
Cov.:
34
AF XY:
0.0187
AC XY:
13547
AN XY:
722602
show subpopulations
Gnomad4 AFR exome
AF:
0.00374
Gnomad4 AMR exome
AF:
0.00683
Gnomad4 ASJ exome
AF:
0.00936
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00195
Gnomad4 FIN exome
AF:
0.00691
Gnomad4 NFE exome
AF:
0.0233
Gnomad4 OTH exome
AF:
0.0139
GnomAD4 genome
AF:
0.0125
AC:
1906
AN:
152264
Hom.:
21
Cov.:
32
AF XY:
0.0106
AC XY:
789
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00462
Gnomad4 AMR
AF:
0.00914
Gnomad4 ASJ
AF:
0.00807
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00451
Gnomad4 NFE
AF:
0.0214
Gnomad4 OTH
AF:
0.0132
Alfa
AF:
0.0195
Hom.:
22
Bravo
AF:
0.0126
TwinsUK
AF:
0.0183
AC:
68
ALSPAC
AF:
0.0223
AC:
86
ESP6500AA
AF:
0.00432
AC:
19
ESP6500EA
AF:
0.0193
AC:
166
ExAC
AF:
0.0122
AC:
1475
Asia WGS
AF:
0.00115
AC:
5
AN:
3478
EpiCase
AF:
0.0213
EpiControl
AF:
0.0206

ClinVar

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

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 11, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 03, 2023- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
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. -
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. -
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.66
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.74
D;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.65
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.84
T;T
MetaRNN
Benign
0.0055
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N;.
MutationTaster
Benign
0.98
N
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-3.0
D;.
REVEL
Benign
0.13
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0040
D;.
Polyphen
0.084
B;.
Vest4
0.033
MPC
0.53
ClinPred
0.065
T
GERP RS
0.26
Varity_R
0.27
gMVP
0.44

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

LitVar

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

Other links and lift over

dbSNP: rs79049330; hg19: chr7-42005588; COSMIC: COSV67895407; API