9-4117942-G-T

Position:

chr9-4117942-G-T

Variant summary

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

The NM_001042413.2(GLIS3):c.1536C>A(p.Asp512Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,060 control chromosomes in the GnomAD database, including 303 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 (★★).

Frequency

Genomes: 𝑓 0.014 ( 36 hom., cov: 31)

Exomes 𝑓: 0.017 ( 267 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.871

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039258897).

BP6

Variant 9-4117942-G-T is Benign according to our data. Variant chr9-4117942-G-T is described in ClinVar as [Benign]. Clinvar id is 129158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-4117942-G-T is described in Lovd as [Benign]. Variant chr9-4117942-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.014 (2133/152280) while in subpopulation SAS AF= 0.0211 (102/4826). AF 95% confidence interval is 0.0181. There are 36 homozygotes in gnomad4. There are 1076 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIS3	NM_001042413.2 linkuse as main transcript	c.1536C>A	p.Asp512Glu	missense_variant	4/11	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8 linkuse as main transcript	c.1536C>A	p.Asp512Glu	missense_variant	4/11	5	NM_001042413.2	ENSP00000371398	P1	Q8NEA6-2

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2136

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0419

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0167

AC:

4187

AN:

251232

Hom.:

AF XY:

0.0180

AC XY:

2450

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0243

Gnomad FIN exome

AF:

0.0391

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0171

AC:

24949

AN:

1461780

Hom.:

267

Cov.:

AF XY:

0.0177

AC XY:

12838

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00385

Gnomad4 ASJ exome

AF:

0.00869

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0249

Gnomad4 FIN exome

AF:

0.0367

Gnomad4 NFE exome

AF:

0.0175

Gnomad4 OTH exome

AF:

0.0138

GnomAD4 genome

AF:

0.0140

AC:

2133

AN:

152280

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1076

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.00575

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0211

Gnomad4 FIN

AF:

0.0419

Gnomad4 NFE

AF:

0.0190

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0167

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0185

AC:

159

ExAC

AF:

0.0173

AC:

2097

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 04, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2016	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GLIS3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 28444304, 31415576) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in GLIS3 gene predisposes to neonatal diabetes mellitus with an extra pancreatic manifestation of hypothyroidism. rs148199056 (p.D512E) also predisposes to early onset diabetes in adults. However, Its significance in predisposition to MODY remains unclear. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Aug 10, 2018

ACMG criteria: (REVEL = 0.123, PP3/3 predictors, BP4,7 predictors = conflicting evidence, not using), BA1 (1.7% overall MAF in gnomAD; 3.97% in EF, 2% in SA and ENF pop), BS2 (58 homozygotes in gnomAD)=benign -

Neonatal diabetes mellitus with congenital hypothyroidism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.080

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

0.96

N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.12

Sift

Benign

0.37

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.19

MutPred

0.30

Gain of disorder (P = 0.1421);.;

MPC

0.025

ClinPred

0.011

GERP RS

3.4

Varity_R

0.049

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over