rs75564360
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2BP4_StrongBP6_Very_StrongBP7BS1
The NM_001042413.2(GLIS3):c.954C>T(p.Thr318=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,614,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 1 hom. )
Consequence
GLIS3
NM_001042413.2 synonymous
NM_001042413.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.765
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 9-4118524-G-A is Benign according to our data. Variant chr9-4118524-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 366988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.765 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (228/152338) while in subpopulation AFR AF= 0.00534 (222/41590). AF 95% confidence interval is 0.00476. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLIS3 | NM_001042413.2 | c.954C>T | p.Thr318= | synonymous_variant | 4/11 | ENST00000381971.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLIS3 | ENST00000381971.8 | c.954C>T | p.Thr318= | synonymous_variant | 4/11 | 5 | NM_001042413.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00148 AC: 225AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000314 AC: 79AN: 251396Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135876
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GnomAD4 exome AF: 0.000148 AC: 216AN: 1461884Hom.: 1 Cov.: 36 AF XY: 0.000107 AC XY: 78AN XY: 727244
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GnomAD4 genome AF: 0.00150 AC: 228AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111AN XY: 74496
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 02, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 21, 2016 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | GLIS3: BP4, BP7 - |
Transitory neonatal diabetes mellitus Benign:1
Benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in GLIS3 predisposes to neonatal diabetes mellitus with an extra pancreatic manifestation of hypothyroidism. It also predisposes to early onset diabetes in adults.However no sufficient evidence is found to ascertain the role of this particular variant rs75564360, yet. - |
GLIS3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 14, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Neonatal diabetes mellitus with congenital hypothyroidism Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at