9-4117942-G-T

Variant names:

• chr9-4117942-G-T
• rs148199056
• NM_001042413.2:c.1536C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.871
• Publications: 10 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 hypothyroidism

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042413.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	NP_001425836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.1071C>A	p.Asp357Glu	missense	Exon 3 of 10	ENSP00000325494.10
	GLIS3	ENST00000467497.6	TSL:1	n.76C>A		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2136 AN: 152162 Hom.: 36 Cov.: 31

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

GnomAD2 exomes AF: 0.0167 AC: 4187 AN: 251232 AF XY: 0.0180

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 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.: 39 AF XY: 0.0177 AC XY: 12838 AN XY: 727188

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.00385 AC: 172 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 227 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0249 AC: 2147 AN: 86258

European-Finnish (FIN) AF: 0.0367 AC: 1955 AN: 53326

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5768

European-Non Finnish (NFE) AF: 0.0175 AC: 19474 AN: 1111992

Other (OTH) AF: 0.0138 AC: 833 AN: 60396

GnomAD4 genome AF: 0.0140 AC: 2133 AN: 152280 Hom.: 36 Cov.: 31 AF XY: 0.0144 AC XY: 1076 AN XY: 74474

African (AFR) AF: 0.00241 AC: 100 AN: 41560

American (AMR) AF: 0.00575 AC: 88 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4826

European-Finnish (FIN) AF: 0.0419 AC: 445 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0190 AC: 1290 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0171 Hom.: 91

Bravo AF: 0.0111

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0185 AC: 159

ExAC AF: 0.0173 AC: 2097

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 18, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLIS3: BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28444304, 31415576)

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diabetes mellitus Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Aug 10, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.87
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.12
Sift	Benign	0.37	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.30		Gain of disorder (P = 0.1421)
MPC		0.025
ClinPred		0.011	T
GERP RS		3.4
Varity_R		0.049
gMVP		0.32
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs148199056; hg19: chr9-4117942;