chr9-4118111-G-T

Position:

chr9-4118111-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042413.2(GLIS3):c.1367C>A(p.Pro456Gln) variant causes a missense change. The variant allele was found at a frequency of 0.614 in 1,527,248 control chromosomes in the GnomAD database, including 289,946 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 29037 hom., cov: 27)

Exomes 𝑓: 0.61 ( 260909 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.11

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:

GLIS3 (HGNC:):

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=5.9029145E-7).

BP6

Variant 9-4118111-G-T is Benign according to our data. Variant chr9-4118111-G-T is described in ClinVar as [Benign]. Clinvar id is 129160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-4118111-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIS3	NM_001042413.2 linkuse as main transcript	c.1367C>A	p.Pro456Gln	missense_variant	4/11	ENST00000381971.8	NP_001035878.1	Q8NEA6-2Q1PHJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8 linkuse as main transcript	c.1367C>A	p.Pro456Gln	missense_variant	4/11	5	NM_001042413.2	ENSP00000371398.3		Q8NEA6-2

Frequencies

GnomAD3 genomes

AF:

0.623

AC:

92567

AN:

148672

Hom.:

29006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.605

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.725

Gnomad ASJ

AF:

0.598

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.656

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.595

Gnomad OTH

AF:

0.631

GnomAD3 exomes

AF:

0.670

AC:

118472

AN:

176820

Hom.:

40401

AF XY:

0.658

AC XY:

63225

AN XY:

96026

show subpopulations

Gnomad AFR exome

AF:

0.623

Gnomad AMR exome

AF:

0.815

Gnomad ASJ exome

AF:

0.628

Gnomad EAS exome

AF:

0.876

Gnomad SAS exome

AF:

0.555

Gnomad FIN exome

AF:

0.681

Gnomad NFE exome

AF:

0.616

Gnomad OTH exome

AF:

0.656

GnomAD4 exome

AF:

0.613

AC:

844347

AN:

1378470

Hom.:

260909

Cov.:

AF XY:

0.611

AC XY:

413524

AN XY:

677288

show subpopulations

Gnomad4 AFR exome

AF:

0.604

Gnomad4 AMR exome

AF:

0.797

Gnomad4 ASJ exome

AF:

0.608

Gnomad4 EAS exome

AF:

0.870

Gnomad4 SAS exome

AF:

0.549

Gnomad4 FIN exome

AF:

0.663

Gnomad4 NFE exome

AF:

0.599

Gnomad4 OTH exome

AF:

0.626

GnomAD4 genome

AF:

0.623

AC:

92653

AN:

148778

Hom.:

29037

Cov.:

AF XY:

0.629

AC XY:

45734

AN XY:

72676

show subpopulations

Gnomad4 AFR

AF:

0.605

Gnomad4 AMR

AF:

0.725

Gnomad4 ASJ

AF:

0.598

Gnomad4 EAS

AF:

0.870

Gnomad4 SAS

AF:

0.549

Gnomad4 FIN

AF:

0.656

Gnomad4 NFE

AF:

0.595

Gnomad4 OTH

AF:

0.632

Alfa

AF:

0.607

Hom.:

34712

TwinsUK

AF:

0.594

AC:

2202

ALSPAC

AF:

0.600

AC:

2312

ESP6500AA

AF:

0.686

AC:

2499

ESP6500EA

AF:

0.661

AC:

4958

ExAC

AF:

0.634

AC:

73042

Asia WGS

AF:

0.694

AC:

2415

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neonatal diabetes mellitus with congenital hypothyroidism

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

Diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in GLIS3 can predispose to neonatal diabetes mellitus with an extra pancreatic manifestation of hypothyroidism. P456Q (rs6415788) also predisposes to early onset diabetes in adults. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.20

T;T

MetaRNN

Benign

5.9e-7

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.2

N;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

2.1

N;N

REVEL

Benign

0.099

Sift

Benign

1.0

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0

B;B

Vest4

0.19

MPC

0.025

ClinPred

0.0023

GERP RS

5.4

Varity_R

0.042

gMVP

0.22

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