NM_001042413.2:c.2338dupC

Variant names:

• chr9-3856143-C-CG
• rs869320723
• NM_001042413.2:c.2338dupC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001042413.2(GLIS3):​c.2338dupC​(p.Arg780ProfsTer79) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R780R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLIS3 NM_001042413.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.35
• 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: 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-3856143-C-CG is Pathogenic according to our data. Variant chr9-3856143-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 1325.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.2338dupC	p.Arg780ProfsTer79	frameshift	Exon 9 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.2338dupC	p.Arg780ProfsTer79	frameshift	Exon 9 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.2338dupC	p.Arg780ProfsTer79	frameshift	Exon 9 of 11	NP_001425836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.2338dupC	p.Arg780ProfsTer79	frameshift	Exon 9 of 11	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.1873dupC	p.Arg625ProfsTer79	frameshift	Exon 8 of 10	ENSP00000325494.10
	GLIS3	ENST00000467497.6	TSL:1	n.878dupC		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neonatal diabetes mellitus with congenital hypothyroidism Pathogenic:1

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=8/192	disease causing (ClinVar)

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: rs869320723; hg19: chr9-3856143;