9-4118393-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001042413.2(GLIS3):c.1085C>A(p.Pro362Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000645 in 1,603,744 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 7 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:5O:1

Conservation

PhyloP100: 4.96

Publications

4 publications found

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 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)

GLIS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006207347).

BP6

Variant 9-4118393-G-T is Benign according to our data. Variant chr9-4118393-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393417.

BS2

High Homozygotes in GnomAd4 at 5 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2 link	c.1085C>A	p.Pro362Gln	missense_variant	Exon 4 of 11	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8 link	c.1085C>A	p.Pro362Gln	missense_variant	Exon 4 of 11	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes

AF:

0.00333

AC:

507

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

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:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000774

AC:

176

AN:

227364

AF XY:

0.000564

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000197

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000363

AC:

527

AN:

1451398

Hom.:

Cov.:

AF XY:

0.000306

AC XY:

221

AN XY:

722222

show subpopulations

African (AFR)

AF:

0.0128

AC:

426

AN:

33348

American (AMR)

AF:

0.000496

AC:

AN:

44388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.0000698

AC:

AN:

85922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46026

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1110382

Other (OTH)

AF:

0.000982

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00333

AC:

508

AN:

152346

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0117

AC:

485

AN:

41586

American (AMR)

AF:

0.000980

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.00393

ESP6500AA

AF:

0.00733

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000943

AC:

112

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Monogenic diabetes

Benign:1

Feb 27, 2018

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 (2 predictors), BP4 (8 predictors), BP5 (found in case with other cause), BS1 (2.11% in ExAC African pop. and 1 hom in ExAC), Note: 9 het, 1 hom in TODAY (1% MAF)=likely benign

Neonatal diabetes mellitus with congenital hypothyroidism

Benign:1

Jan 13, 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.

Transitory neonatal diabetes mellitus

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain risk allele

Review Status:criteria provided, single submitter

Collection Method:research

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 rs146131512, yet.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.0062

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

5.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.70

N;N

REVEL

Benign

0.063

Sift

Benign

0.081

T;D

Sift4G

Benign

0.28

T;T

Vest4

0.22

ClinPred

0.015

GERP RS

4.7

Varity_R

0.055

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over