rs117802495

Variant names:

• chr9-4286255-G-A
• rs117802495
• NM_001042413.2:c.171C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001042413.2(GLIS3):​c.171C>T​(p.Asn57Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,230 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (15 hom., cov: 33)
  • Exomes 𝑓: 0.012 (141 hom.)
• Consequence: GLIS3 NM_001042413.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.06

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-4286255-G-A is Benign according to our data. Variant chr9-4286255-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-4286255-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.06 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.171C>T	p.Asn57Asn	synonymous_variant	Exon 2 of 11	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8	c.171C>T	p.Asn57Asn	synonymous_variant	Exon 2 of 11	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.00916 AC: 1395 AN: 152226 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00926 AC: 2308 AN: 249360 Hom.: 23 AF XY: 0.00920 AC XY: 1245 AN XY: 135318

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00776

GnomAD4 exome AF: 0.0119 AC: 17388 AN: 1461886 Hom.: 141 Cov.: 32 AF XY: 0.0117 AC XY: 8492 AN XY: 727244

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.0259

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00833

GnomAD4 genome AF: 0.00915 AC: 1394 AN: 152344 Hom.: 15 Cov.: 33 AF XY: 0.00944 AC XY: 703 AN XY: 74494

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.0112 Hom.: 9

Bravo AF: 0.00732

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLIS3: BP4, BP7, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Oct 01, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neonatal diabetes mellitus with congenital hypothyroidism Benign:1

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. -

Transitory neonatal diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in GLIS3 predisposes to neonatal diabetes mellitus with an extra pancreatic manifestation of hypothyroidism. It also predisposes to early onset diabetes in adults.However no sufficient evidence is found to ascertain the role of this particular variant rs117802495, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.5
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117802495; hg19: chr9-4286255;