9-4118208-A-G

Variant names:

• chr9-4118208-A-G
• rs806052
• NM_001042413.2:c.1270T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042413.2(GLIS3):​c.1270T>C​(p.Ser424Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,585,008 control chromosomes in the GnomAD database, including 792,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S424L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 1.0 (76007 hom., cov: 34)
  • Exomes 𝑓: 1.0 (716201 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.854
• Publications: 26 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.210914E-7).
• BP6: Variant 9-4118208-A-G is Benign according to our data. Variant chr9-4118208-A-G is described in ClinVar as Benign. ClinVar VariationId is 129159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042413.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	NP_001425836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.805T>C	p.Ser269Pro	missense	Exon 3 of 10	ENSP00000325494.10
	GLIS3	ENST00000491889.6	TSL:1	n.*633T>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1

Frequencies

GnomAD3 genomes AF: 0.999 AC: 152053 AN: 152208 Hom.: 75949 Cov.: 34

Gnomad AFR AF: 0.996

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 202267 AN: 202322 AF XY: 1.00

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1432543 AN: 1432684 Hom.: 716201 Cov.: 71 AF XY: 1.00 AC XY: 709304 AN XY: 709358

African (AFR) AF: 0.996 AC: 32833 AN: 32952

American (AMR) AF: 1.00 AC: 41887 AN: 41892

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 24802 AN: 24802

East Asian (EAS) AF: 1.00 AC: 39016 AN: 39016

South Asian (SAS) AF: 1.00 AC: 82190 AN: 82190

European-Finnish (FIN) AF: 1.00 AC: 49809 AN: 49810

Middle Eastern (MID) AF: 1.00 AC: 5462 AN: 5462

European-Non Finnish (NFE) AF: 1.00 AC: 1097583 AN: 1097590

Other (OTH) AF: 1.00 AC: 58961 AN: 58970

GnomAD4 genome AF: 0.999 AC: 152169 AN: 152324 Hom.: 76007 Cov.: 34 AF XY: 0.999 AC XY: 74404 AN XY: 74476

African (AFR) AF: 0.996 AC: 41437 AN: 41590

American (AMR) AF: 1.00 AC: 15309 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5156 AN: 5156

South Asian (SAS) AF: 1.00 AC: 4834 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68014 AN: 68014

Other (OTH) AF: 1.00 AC: 2113 AN: 2114

Alfa AF: 0.999 Hom.: 28119

Bravo AF: 0.999

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.996 AC: 3063

ESP6500EA AF: 1.00 AC: 6261

ExAC AF: 0.999 AC: 113004

Asia WGS AF: 0.999 AC: 3470 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28444304)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Neonatal diabetes mellitus with congenital hypothyroidism Benign:3

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.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.31
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	7.2e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.42	N
PhyloP100		-0.85
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.0030
Sift	Benign	0.65	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.029
ClinPred		0.00091	T
GERP RS		-2.6
Varity_R		0.043
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs806052; hg19: chr9-4118208; COSMIC: COSV60924689; COSMIC: COSV60924689;