NM_001042413.2:c.1973C>G
Variant names:
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_001042413.2(GLIS3):c.1973C>G(p.Ala658Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A658E) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
GLIS3
NM_001042413.2 missense
NM_001042413.2 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 2.27
Publications
1 publications found
Genes affected
GLIS3 (HGNC:28510): (GLIS family zinc finger 3) This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear protein with five C2H2-type zinc finger domains. This protein functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, the thyroid, eye, liver and kidney. Mutations in this gene have been associated with neonatal diabetes and congenital hypothyroidism (NDH). Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only two have been determined. [provided by RefSeq, Jul 2008]
GLIS3 Gene-Disease associations (from GenCC):
- neonatal diabetes mellitus with congenital hypothyroidismInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Tourette syndromeInheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23424765).
BP6
Variant 9-3932370-G-C is Benign according to our data. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529. Variant chr9-3932370-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 549529.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 151928Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151928
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459710Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726314 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1459710
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726314
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33432
American (AMR)
AF:
AC:
1
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26110
East Asian (EAS)
AF:
AC:
0
AN:
39658
South Asian (SAS)
AF:
AC:
0
AN:
86226
European-Finnish (FIN)
AF:
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1110102
Other (OTH)
AF:
AC:
2
AN:
60310
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000658 AC: 1AN: 151928Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74214 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
151928
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74214
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41260
American (AMR)
AF:
AC:
1
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5190
South Asian (SAS)
AF:
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68002
Other (OTH)
AF:
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Sep 14, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.1508C>G (p.A503G) alteration is located in exon 5 (coding exon 4) of the GLIS3 gene. This alteration results from a C to G substitution at nucleotide position 1508, causing the alanine (A) at amino acid position 503 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Neonatal diabetes mellitus with congenital hypothyroidism Uncertain:1
Dec 31, 2023
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Monogenic diabetes Benign:1
Oct 06, 2017
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research
ACMG Criteria:PP3 (4 predictors), BP4 (6 predictors), PM2, BP1 (missense in gene with truncating cause disease) -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Loss of MoRF binding (P = 0.1188);.;
MVP
MPC
0.10
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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