9-4206388-A-G

Variant names:

• chr9-4206388-A-G
• rs7048915
• NM_001042413.2:c.388+79650T>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+79650T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,144 control chromosomes in the GnomAD database, including 38,690 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 0.70 (38690 hom., cov: 32)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.388+79650T>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+79650T>C		intron_variant	Intron 2 of 10	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106800 AN: 152024 Hom.: 38672 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.757

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.673

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.718

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

GnomAD4 genome AF: 0.702 AC: 106862 AN: 152144 Hom.: 38690 Cov.: 32 AF XY: 0.709 AC XY: 52772 AN XY: 74388

African (AFR) AF: 0.526 AC: 21810 AN: 41480

American (AMR) AF: 0.770 AC: 11766 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 2630 AN: 3472

East Asian (EAS) AF: 0.973 AC: 5046 AN: 5188

South Asian (SAS) AF: 0.908 AC: 4376 AN: 4820

European-Finnish (FIN) AF: 0.780 AC: 8257 AN: 10582

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.745 AC: 50629 AN: 67996

Other (OTH) AF: 0.717 AC: 1515 AN: 2112

Alfa AF: 0.732 Hom.: 123287

Bravo AF: 0.693

Asia WGS AF: 0.895 AC: 3108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	9.5
DANN	Benign	0.70
PhyloP100		0.068
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: rs7048915; hg19: chr9-4206388;