9-4291747-C-G

Variant names:

• chr9-4291747-C-G
• rs7020673
• NM_001042413.2:c.-98-5224G>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.-98-5224G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 151,948 control chromosomes in the GnomAD database, including 29,794 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 0.61 (29794 hom., cov: 32)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0440
• Publications: 79 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.-98-5224G>C		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.-98-5224G>C		intron_variant	Intron 1 of 10	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92558 AN: 151832 Hom.: 29764 Cov.: 32

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.610 AC: 92642 AN: 151948 Hom.: 29794 Cov.: 32 AF XY: 0.607 AC XY: 45076 AN XY: 74250

African (AFR) AF: 0.837 AC: 34722 AN: 41502

American (AMR) AF: 0.571 AC: 8718 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2028 AN: 3472

East Asian (EAS) AF: 0.477 AC: 2462 AN: 5164

South Asian (SAS) AF: 0.567 AC: 2732 AN: 4820

European-Finnish (FIN) AF: 0.509 AC: 5357 AN: 10532

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34638 AN: 67878

Other (OTH) AF: 0.589 AC: 1239 AN: 2104

Alfa AF: 0.406 Hom.: 996

Bravo AF: 0.623

Asia WGS AF: 0.551 AC: 1920 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.4
DANN	Benign	0.58
PhyloP100		0.044
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: rs7020673; hg19: chr9-4291747;