rs35154632

chr9-4118540-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G313R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (66 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.02

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS3	NM_001042413.2	c.938G>C	p.Gly313Ala	missense_variant	4/11	ENST00000381971.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS3	ENST00000381971.8	c.938G>C	p.Gly313Ala	missense_variant	4/11	5	NM_001042413.2	P1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1619 AN: 152202 Hom.: 8 Cov.: 32

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.: 14 AF XY: 0.00726 AC XY: 987 AN XY: 135910

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.: 66 Cov.: 36 AF XY: 0.00880 AC XY: 6399 AN XY: 727242

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.: 8 Cov.: 32 AF XY: 0.0112 AC XY: 836 AN XY: 74490

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.: 6

Bravo AF: 0.00997

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00775 AC: 941

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	GLIS3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
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	T
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

Other links and lift over

dbSNP: rs35154632; hg19: chr9-4118540;