chr9-4104571-C-G

Variant names:

• chr9-4104571-C-G
• rs1074449
• NM_001042413.2:c.1710+13197G>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.1710+13197G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 152,092 control chromosomes in the GnomAD database, including 6,207 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 0.27 (6207 hom., cov: 32)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• 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=-0.71).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.1710+13197G>C		intron_variant	Intron 4 of 10	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8	c.1710+13197G>C		intron_variant	Intron 4 of 10	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40610 AN: 151976 Hom.: 6207 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.271

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

GnomAD4 genome AF: 0.267 AC: 40604 AN: 152092 Hom.: 6207 Cov.: 32 AF XY: 0.268 AC XY: 19897 AN XY: 74360

African (AFR) AF: 0.128 AC: 5335 AN: 41542

American (AMR) AF: 0.268 AC: 4090 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1017 AN: 3464

East Asian (EAS) AF: 0.206 AC: 1063 AN: 5158

South Asian (SAS) AF: 0.412 AC: 1981 AN: 4812

European-Finnish (FIN) AF: 0.323 AC: 3423 AN: 10586

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22546 AN: 67956

Other (OTH) AF: 0.269 AC: 569 AN: 2114

Alfa AF: 0.186 Hom.: 404

Bravo AF: 0.254

Asia WGS AF: 0.301 AC: 1043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.5
DANN	Benign	0.82
PhyloP100		-1.6
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: rs1074449; hg19: chr9-4104571;