rs76094493

chr9-3828379-G-Achr9-3828379-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042413.2(GLIS3):c.2686C>T(p.Leu896Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,613,564 control chromosomes in the GnomAD database, including 630 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. L896L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (360 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (270 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.633

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016325116).
• BP6: Variant 9-3828379-G-A is Benign according to our data. Variant chr9-3828379-G-A is described in ClinVar as [Benign]. Clinvar id is 129155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-3828379-G-A is described in Lovd as [Benign]. Variant chr9-3828379-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS3	NM_001042413.2	c.2686C>T	p.Leu896Phe	missense_variant	11/11	ENST00000381971.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS3	ENST00000381971.8	c.2686C>T	p.Leu896Phe	missense_variant	11/11	5	NM_001042413.2	P1

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5500 AN: 152148 Hom.: 360 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.00919 AC: 2300 AN: 250170 Hom.: 125 AF XY: 0.00634 AC XY: 858 AN XY: 135290

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00353 AC: 5155 AN: 1461298 Hom.: 270 Cov.: 31 AF XY: 0.00300 AC XY: 2179 AN XY: 726940

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.00622

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.00744

GnomAD4 genome AF: 0.0362 AC: 5507 AN: 152266 Hom.: 360 Cov.: 33 AF XY: 0.0339 AC XY: 2527 AN XY: 74462

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.00717 Hom.: 86

Bravo AF: 0.0403

ESP6500AA AF: 0.122 AC: 539

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0113 AC: 1376

Asia WGS AF: 0.00636 AC: 22 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 14, 2018

ACMG criteria: BP4 (REVEL 0.045 + 7 predictors), BA1 (12% in Africans), BS2 (192 homozygotes in gnomAD)= benign -

Neonatal diabetes mellitus with congenital hypothyroidism Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

GLIS3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.0038
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.68	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.86	N;N
REVEL	Benign	0.045
Sift	Benign	0.21	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.88	P;P
Vest4		0.071
MPC		0.22
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.090
gMVP		0.13

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

Other links and lift over

dbSNP: rs76094493; hg19: chr9-3828379; COSMIC: COSV60930913;