9-3862693-G-A

Variant names:

• chr9-3862693-G-A
• rs10973877
• NM_001042413.2:c.2298-6509C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042413.2(GLIS3):​c.2298-6509C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 151,918 control chromosomes in the GnomAD database, including 22,272 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22272 hom., cov: 31)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.750
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.874 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.2298-6509C>T		intron	N/A	NP_001035878.1
	GLIS3	NM_001438906.1		c.2298-6509C>T		intron	N/A	NP_001425835.1
	GLIS3	NM_001438907.1		c.2298-6509C>T		intron	N/A	NP_001425836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.2298-6509C>T		intron	N/A	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.1833-6509C>T		intron	N/A	ENSP00000325494.10
	GLIS3	ENST00000467497.6	TSL:1	n.838-6509C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81161 AN: 151800 Hom.: 22258 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.896

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.573

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.535 AC: 81209 AN: 151918 Hom.: 22272 Cov.: 31 AF XY: 0.534 AC XY: 39677 AN XY: 74232

African (AFR) AF: 0.448 AC: 18542 AN: 41426

American (AMR) AF: 0.613 AC: 9360 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2083 AN: 3466

East Asian (EAS) AF: 0.895 AC: 4616 AN: 5156

South Asian (SAS) AF: 0.500 AC: 2408 AN: 4814

European-Finnish (FIN) AF: 0.444 AC: 4679 AN: 10550

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.552 AC: 37526 AN: 67934

Other (OTH) AF: 0.575 AC: 1208 AN: 2102

Alfa AF: 0.543 Hom.: 30494

Bravo AF: 0.550

Asia WGS AF: 0.640 AC: 2225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.0
DANN	Benign	0.88
PhyloP100		-0.75
Mutation Taster		=100/0	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: rs10973877; hg19: chr9-3862693; COSMIC: COSV60926100;