9-3929424-C-T

Variant names:

• chr9-3929424-C-T
• rs514716
• NM_001042413.2:c.1983+2936G>A

Variant summary

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

The NM_001042413.2(GLIS3):​c.1983+2936G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 152,062 control chromosomes in the GnomAD database, including 52,067 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 0.83 (52067 hom., cov: 30)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.1983+2936G>A		intron_variant	Intron 6 of 10	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8	c.1983+2936G>A		intron_variant	Intron 6 of 10	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125445 AN: 151944 Hom.: 52040 Cov.: 30

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.873

Gnomad OTH AF: 0.821

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

GnomAD4 genome AF: 0.826 AC: 125529 AN: 152062 Hom.: 52067 Cov.: 30 AF XY: 0.823 AC XY: 61120 AN XY: 74306

African (AFR) AF: 0.754 AC: 31267 AN: 41450

American (AMR) AF: 0.815 AC: 12442 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 3066 AN: 3468

East Asian (EAS) AF: 0.675 AC: 3482 AN: 5156

South Asian (SAS) AF: 0.829 AC: 3986 AN: 4810

European-Finnish (FIN) AF: 0.858 AC: 9082 AN: 10582

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.873 AC: 59352 AN: 68004

Other (OTH) AF: 0.820 AC: 1732 AN: 2112

Alfa AF: 0.853 Hom.: 132177

Bravo AF: 0.820

Asia WGS AF: 0.720 AC: 2504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.76
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs514716; hg19: chr9-3929424;