rs117802495

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 Benign/Likely_benign. ClinVar VariationId is 257273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.06 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 15 AR,Unknown gene

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.171C>T	p.Asn57Asn	synonymous	Exon 2 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.171C>T	p.Asn57Asn	synonymous	Exon 2 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.171C>T	p.Asn57Asn	synonymous	Exon 2 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.171C>T	p.Asn57Asn	synonymous	Exon 2 of 11	ENSP00000371398.3
	GLIS3	ENST00000477901.5	TSL:1	c.171C>T	p.Asn57Asn	synonymous	Exon 2 of 4	ENSP00000417794.1
	GLIS3	ENST00000481827.5	TSL:1	c.171C>T	p.Asn57Asn	synonymous	Exon 2 of 4	ENSP00000417883.1

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

GnomAD2 exomes AF: 0.00926 AC: 2308 AN: 249360 AF XY: 0.00920

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 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

African (AFR) AF: 0.00173 AC: 58 AN: 33480

American (AMR) AF: 0.00320 AC: 143 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00177 AC: 153 AN: 86258

European-Finnish (FIN) AF: 0.0259 AC: 1386 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0136 AC: 15122 AN: 1112004

Other (OTH) AF: 0.00833 AC: 503 AN: 60396

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

African (AFR) AF: 0.00212 AC: 88 AN: 41590

American (AMR) AF: 0.00366 AC: 56 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0309 AC: 328 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 900 AN: 68034

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Neonatal diabetes mellitus with congenital hypothyroidism (1)
-	-	1	Transitory neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.5
DANN	Benign	0.70
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs117802495; hg19: chr9-4286255;