chr9-4335668-G-A

Variant names:

• chr9-4335668-G-A
• rs4131424
• ENST00000471664.1:n.264+11413C>T

Variant summary

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

The ENST00000471664.1(GLIS3):​n.264+11413C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,004 control chromosomes in the GnomAD database, including 2,005 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 0.16 (2005 hom., cov: 31)
• Consequence: GLIS3 ENST00000471664.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.556
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	XM_047422890.1	c.133+11413C>T		intron_variant	Intron 3 of 11		XP_047278846.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000471664.1	n.264+11413C>T		intron_variant	Intron 2 of 4	1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24303 AN: 151886 Hom.: 2000 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.160 AC: 24315 AN: 152004 Hom.: 2005 Cov.: 31 AF XY: 0.157 AC XY: 11636 AN XY: 74298

African (AFR) AF: 0.203 AC: 8401 AN: 41428

American (AMR) AF: 0.123 AC: 1878 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 559 AN: 3472

East Asian (EAS) AF: 0.119 AC: 615 AN: 5150

South Asian (SAS) AF: 0.118 AC: 566 AN: 4810

European-Finnish (FIN) AF: 0.112 AC: 1180 AN: 10576

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10466 AN: 67966

Other (OTH) AF: 0.177 AC: 373 AN: 2110

Alfa AF: 0.159 Hom.: 3476

Bravo AF: 0.161

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.35
DANN	Benign	0.72
PhyloP100		-0.56

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4131424; hg19: chr9-4335668;