rs35154632

Positions:

chr9-4118540-C-G

Variant summary

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

The NM_001042413.2(GLIS3):c.938G>C(p.Gly313Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00913 in 1,614,206 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 66 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.02

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=0.009075195).

BP6

Variant 9-4118540-C-G is Benign according to our data. Variant chr9-4118540-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-4118540-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1628/152320) while in subpopulation AFR AF= 0.0153 (636/41576). AF 95% confidence interval is 0.0143. There are 8 homozygotes in gnomad4. There are 836 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLIS3	NM_001042413.2 linkuse as main transcript	c.938G>C	p.Gly313Ala	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.938G>C	p.Gly313Ala	missense_variant	4/11	5	NM_001042413.2	ENSP00000371398	P1	Q8NEA6-2

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1619

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00680

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00733

AC:

1843

AN:

251470

Hom.:

AF XY:

0.00726

AC XY:

987

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00337

Gnomad SAS exome

AF:

0.00487

Gnomad FIN exome

AF:

0.00674

Gnomad NFE exome

AF:

0.00909

Gnomad OTH exome

AF:

0.00928

GnomAD4 exome

AF:

0.00897

AC:

13116

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00880

AC XY:

6399

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0151

Gnomad4 AMR exome

AF:

0.00440

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.00482

Gnomad4 FIN exome

AF:

0.00717

Gnomad4 NFE exome

AF:

0.00995

Gnomad4 OTH exome

AF:

0.00796

GnomAD4 genome

AF:

0.0107

AC:

1628

AN:

152320

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

836

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0153

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00848

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00952

Hom.:

Bravo

AF:

0.00997

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.0200

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00775

AC:

941

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00856

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	GLIS3: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	This variant is associated with the following publications: (PMID: 32425884, 31287502) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Neonatal diabetes mellitus with congenital hypothyroidism

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 01, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 01, 2019

ACMG criteria: BA1 (1.63% in gnomAD African, 0.7% overall), BS2 (17 homozygotes in gnomAD)=benign (REVEL 0.206 +PP3/7 predictors + BP4/3 predictors: conflicting evidence, not using) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.087

T;T

Polyphen

1.0

D;D

Vest4

0.75

MVP

0.80

MPC

0.22

ClinPred

0.018

GERP RS

5.6

Varity_R

0.36

gMVP

0.46

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