9-4237546-A-G

Variant names:

• chr9-4237546-A-G
• rs2224492
• NM_001042413.2:c.388+48492T>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+48492T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,190 control chromosomes in the GnomAD database, including 5,929 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 0.25 (5929 hom., cov: 32)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• Publications: 8 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 (EAS) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.388+48492T>C		intron_variant	Intron 2 of 10	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8	c.388+48492T>C		intron_variant	Intron 2 of 10	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38749 AN: 152072 Hom.: 5937 Cov.: 32

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.291

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

GnomAD4 genome AF: 0.255 AC: 38745 AN: 152190 Hom.: 5929 Cov.: 32 AF XY: 0.256 AC XY: 19072 AN XY: 74402

African (AFR) AF: 0.0770 AC: 3202 AN: 41574

American (AMR) AF: 0.298 AC: 4562 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3472

East Asian (EAS) AF: 0.342 AC: 1772 AN: 5176

South Asian (SAS) AF: 0.272 AC: 1311 AN: 4816

European-Finnish (FIN) AF: 0.306 AC: 3240 AN: 10578

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22296 AN: 67984

Other (OTH) AF: 0.289 AC: 609 AN: 2104

Alfa AF: 0.288 Hom.: 3662

Bravo AF: 0.251

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.6
DANN	Benign	0.55
PhyloP100		0.11
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: rs2224492; hg19: chr9-4237546; COSMIC: COSV67942880;