chr9-4118287-C-G

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.1191G>C(p.Gln397His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,583,390 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q397R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.33

Publications

3 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=0.009463966).

BP6

Variant 9-4118287-C-G is Benign according to our data. Variant chr9-4118287-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393416.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2 link	c.1191G>C	p.Gln397His	missense_variant	Exon 4 of 11	ENST00000381971.8	NP_001035878.1	Q8NEA6-2Q1PHJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8 link	c.1191G>C	p.Gln397His	missense_variant	Exon 4 of 11	5	NM_001042413.2	ENSP00000371398.3		Q8NEA6-2

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

264

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00260

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00222

AC:

411

AN:

185294

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.000512

Gnomad AMR exome

AF:

0.000679

Gnomad ASJ exome

AF:

0.00551

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00332

Gnomad NFE exome

AF:

0.00358

Gnomad OTH exome

AF:

0.00186

GnomAD4 exome

AF:

0.00304

AC:

4352

AN:

1431066

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2103

AN XY:

709550

show subpopulations

African (AFR)

AF:

0.000334

AC:

AN:

32980

American (AMR)

AF:

0.000685

AC:

AN:

40870

Ashkenazi Jewish (ASJ)

AF:

0.00557

AC:

142

AN:

25502

East Asian (EAS)

AF:

0.00

AC:

AN:

38342

South Asian (SAS)

AF:

0.000157

AC:

AN:

82954

European-Finnish (FIN)

AF:

0.00308

AC:

146

AN:

47478

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.00353

AC:

3878

AN:

1098178

Other (OTH)

AF:

0.00225

AC:

133

AN:

59156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

301

602

903

1204

1505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.00173

AC:

264

AN:

152324

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

133

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41588

American (AMR)

AF:

0.000523

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00260

AC:

177

AN:

68008

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

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:

0.00235

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000990

AC:

ExAC

AF:

0.00192

AC:

221

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Uncertain:1

Jul 07, 2016

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria: PP3, BP4 -

GLIS3-related disorder

Benign:1

Jan 17, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0095

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

1.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.058

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.17

T;T

Polyphen

0.49

P;P

Vest4

0.57

MutPred

0.28

Loss of solvent accessibility (P = 0.1922);.;

MVP

0.76

MPC

0.21

ClinPred

0.024

GERP RS

4.7

Varity_R

0.30

gMVP

0.49

Mutation Taster

=97/3

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