9-4267209-A-G

Variant names:

• chr9-4267209-A-G
• rs1571583
• NM_001042413.2:c.388+18829T>C

Variant summary

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

The NM_001042413.2(GLIS3):​c.388+18829T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 152,038 control chromosomes in the GnomAD database, including 44,235 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 0.76 (44235 hom., cov: 30)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 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.388+18829T>C		intron	N/A	NP_001035878.1
	GLIS3	NM_001438906.1		c.388+18829T>C		intron	N/A	NP_001425835.1
	GLIS3	NM_001438907.1		c.388+18829T>C		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.388+18829T>C		intron	N/A	ENSP00000371398.3
	GLIS3	ENST00000477901.5	TSL:1	c.388+18829T>C		intron	N/A	ENSP00000417794.1
	GLIS3	ENST00000481827.5	TSL:1	c.388+18829T>C		intron	N/A	ENSP00000417883.1

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115504 AN: 151920 Hom.: 44194 Cov.: 30

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.753

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

GnomAD4 genome AF: 0.760 AC: 115595 AN: 152038 Hom.: 44235 Cov.: 30 AF XY: 0.758 AC XY: 56335 AN XY: 74340

African (AFR) AF: 0.788 AC: 32641 AN: 41432

American (AMR) AF: 0.784 AC: 11980 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2137 AN: 3470

East Asian (EAS) AF: 0.619 AC: 3195 AN: 5164

South Asian (SAS) AF: 0.553 AC: 2662 AN: 4812

European-Finnish (FIN) AF: 0.813 AC: 8608 AN: 10588

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.766 AC: 52044 AN: 67982

Other (OTH) AF: 0.753 AC: 1589 AN: 2110

Alfa AF: 0.753 Hom.: 86833

Bravo AF: 0.761

Asia WGS AF: 0.606 AC: 2109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.72
PhyloP100		1.7
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: rs1571583; hg19: chr9-4267209;