NM_001042413.2:c.232C>G

Variant names:

• chr9-4286194-G-C
• rs148168366
• NM_001042413.2:c.232C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001042413.2(GLIS3):​c.232C>G​(p.Arg78Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3 O:1
• Conservation: PhyloP100: 1.75
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048917234).
• BP6: Variant 9-4286194-G-C is Benign according to our data. Variant chr9-4286194-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393419.

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.232C>G	p.Arg78Gly	missense	Exon 2 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.232C>G	p.Arg78Gly	missense	Exon 2 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.232C>G	p.Arg78Gly	missense	Exon 2 of 11	NP_001425836.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.232C>G	p.Arg78Gly	missense	Exon 2 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000477901.5	TSL:1	c.232C>G	p.Arg78Gly	missense	Exon 2 of 4	ENSP00000417794.1	Q1PHJ8
	GLIS3	ENST00000481827.5	TSL:1	c.232C>G	p.Arg78Gly	missense	Exon 2 of 4	ENSP00000417883.1	Q1PHJ8

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000393 AC: 98 AN: 249514 AF XY: 0.000259

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89 AN XY: 727246

African (AFR) AF: 0.00448 AC: 150 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1112008

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74480

African (AFR) AF: 0.00563 AC: 234 AN: 41580

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.00179

ESP6500AA AF: 0.00463 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000537 AC: 65

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Neonatal diabetes mellitus with congenital hypothyroidism (2)
-	1	1	not provided (2)
-	-	1	GLIS3-related disorder (1)
-	1	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.96	T
PhyloP100		1.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.026
Sift	Benign	0.19	T
Sift4G	Benign	0.43	T
Polyphen		0.0030	B
Vest4		0.20
MVP		0.29
MPC		0.030
ClinPred		0.014	T
GERP RS		4.9
gMVP		0.15
Mutation Taster		=97/3	polymorphism

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: rs148168366; hg19: chr9-4286194;