rs10758594

Variant names:

• chr9-4295583-A-G
• rs10758594
• NM_001042413.2:c.-99+3838T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-4295583-A-G
• chr9-4295583-A-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.-99+3838T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 151,984 control chromosomes in the GnomAD database, including 17,292 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 0.46 (17292 hom., cov: 32)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.20
• Publications: 14 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.565 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.-99+3838T>C		intron	N/A	NP_001035878.1
	GLIS3	NM_001438906.1		c.-99+2801T>C		intron	N/A	NP_001425835.1
	GLIS3	NM_001438907.1		c.-99+2697T>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.-99+3838T>C		intron	N/A	ENSP00000371398.3
	GLIS3	ENST00000477901.5	TSL:1	c.-99+3838T>C		intron	N/A	ENSP00000417794.1
	GLIS3	ENST00000481827.5	TSL:1	c.-99+2801T>C		intron	N/A	ENSP00000417883.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69248 AN: 151864 Hom.: 17291 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.474

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

GnomAD4 genome AF: 0.456 AC: 69286 AN: 151984 Hom.: 17292 Cov.: 32 AF XY: 0.456 AC XY: 33852 AN XY: 74282

African (AFR) AF: 0.244 AC: 10135 AN: 41472

American (AMR) AF: 0.446 AC: 6806 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1705 AN: 3468

East Asian (EAS) AF: 0.446 AC: 2302 AN: 5162

South Asian (SAS) AF: 0.479 AC: 2306 AN: 4812

European-Finnish (FIN) AF: 0.556 AC: 5851 AN: 10532

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.569 AC: 38687 AN: 67946

Other (OTH) AF: 0.471 AC: 997 AN: 2116

Alfa AF: 0.527 Hom.: 35613

Bravo AF: 0.439

Asia WGS AF: 0.456 AC: 1585 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.064
DANN	Benign	0.41
PhyloP100		-3.2
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: rs10758594; hg19: chr9-4295583; COSMIC: COSV67943002; COSMIC: COSV67943002;