9-4083665-T-G

Variant names:

• chr9-4083665-T-G
• rs6476804
• NM_001042413.2:c.1710+34103A>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+34103A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 151,988 control chromosomes in the GnomAD database, including 12,693 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 0.41 (12693 hom., cov: 32)
• Consequence: GLIS3 NM_001042413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.123
• 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: Ambry Genetics, Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 (AMR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042413.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.1710+34103A>C		intron	N/A	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.1710+34103A>C		intron	N/A	NP_001425835.1
	GLIS3	NM_001438907.1		c.1710+34103A>C		intron	N/A	NP_001425836.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.1710+34103A>C		intron	N/A	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.1245+34103A>C		intron	N/A	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000467497.6	TSL:1	n.250+34103A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62226 AN: 151868 Hom.: 12676 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.417

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

GnomAD4 genome AF: 0.410 AC: 62295 AN: 151988 Hom.: 12693 Cov.: 32 AF XY: 0.409 AC XY: 30390 AN XY: 74294

African (AFR) AF: 0.384 AC: 15901 AN: 41438

American (AMR) AF: 0.438 AC: 6681 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1633 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1976 AN: 5164

South Asian (SAS) AF: 0.342 AC: 1650 AN: 4818

European-Finnish (FIN) AF: 0.413 AC: 4354 AN: 10546

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28818 AN: 67972

Other (OTH) AF: 0.415 AC: 875 AN: 2110

Alfa AF: 0.422 Hom.: 35454

Bravo AF: 0.411

Asia WGS AF: 0.359 AC: 1251 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.8
DANN	Benign	0.43
PhyloP100		-0.12
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: rs6476804; hg19: chr9-4083665;