rs10814916

Variant names:

• chr9-4293150-A-C
• rs10814916
• NM_001042413.2:c.-99+6271T>G

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+6271T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 152,072 control chromosomes in the GnomAD database, including 24,606 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 0.56 (24606 hom., cov: 33)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.618
• Publications: 63 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.-99+6271T>G		intron_variant	Intron 1 of 10	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8	c.-99+6271T>G		intron_variant	Intron 1 of 10	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85679 AN: 151954 Hom.: 24565 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.575

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.556

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

GnomAD4 genome AF: 0.564 AC: 85768 AN: 152072 Hom.: 24606 Cov.: 33 AF XY: 0.564 AC XY: 41909 AN XY: 74336

African (AFR) AF: 0.677 AC: 28085 AN: 41482

American (AMR) AF: 0.530 AC: 8105 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 1992 AN: 3464

East Asian (EAS) AF: 0.462 AC: 2392 AN: 5174

South Asian (SAS) AF: 0.551 AC: 2652 AN: 4810

European-Finnish (FIN) AF: 0.526 AC: 5563 AN: 10580

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35041 AN: 67960

Other (OTH) AF: 0.560 AC: 1181 AN: 2110

Alfa AF: 0.537 Hom.: 43756

Bravo AF: 0.570

Asia WGS AF: 0.531 AC: 1847 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		-0.62
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: rs10814916; hg19: chr9-4293150;