Genetic Variant GLIS3:p.Asp512Glu (chr9-4117942-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001042413.2(GLIS3):c.1536C>A(p.Asp512Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,060 control chromosomes in the GnomAD database, including 303 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 36 hom., cov: 31)

Exomes 𝑓: 0.017 ( 267 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.871

Publications

10 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, Ambry Genetics
Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GLIS3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001042413.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039258897).

BP6

Variant 9-4117942-G-T is Benign according to our data. Variant chr9-4117942-G-T is described in ClinVar as Benign. ClinVar VariationId is 129158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.014 (2133/152280) while in subpopulation SAS AF = 0.0211 (102/4826). AF 95% confidence interval is 0.0181. There are 36 homozygotes in GnomAd4. There are 1076 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR,Unknown gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLIS3	NM_001042413.2	MANE Select	c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	NP_001035878.1	Q8NEA6-2
GLIS3	NM_001438906.1		c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	NP_001425835.1
GLIS3	NM_001438907.1		c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	NP_001425836.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.1536C>A	p.Asp512Glu	missense	Exon 4 of 11	ENSP00000371398.3	Q8NEA6-2
GLIS3	ENST00000324333.14	TSL:1	c.1071C>A	p.Asp357Glu	missense	Exon 3 of 10	ENSP00000325494.10	Q8NEA6-1
GLIS3	ENST00000467497.6	TSL:1	n.76C>A		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2136

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0419

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0167

AC:

4187

AN:

251232

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0391

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0171

AC:

24949

AN:

1461780

Hom.:

267

Cov.:

AF XY:

0.0177

AC XY:

12838

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33480

American (AMR)

AF:

0.00385

AC:

172

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00869

AC:

227

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0249

AC:

2147

AN:

86258

European-Finnish (FIN)

AF:

0.0367

AC:

1955

AN:

53326

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0175

AC:

19474

AN:

1111992

Other (OTH)

AF:

0.0138

AC:

833

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1469

2939

4408

5878

7347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0140

AC:

2133

AN:

152280

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1076

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00241

AC:

100

AN:

41560

American (AMR)

AF:

0.00575

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0211

AC:

102

AN:

4826

European-Finnish (FIN)

AF:

0.0419

AC:

445

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1290

AN:

68032

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0171

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0162

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Diabetes mellitus (1)

Monogenic diabetes (1)

Neonatal diabetes mellitus with congenital hypothyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.080

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.97

PhyloP100

0.87

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.24

REVEL

Benign

0.12

Sift

Benign

0.37

Sift4G

Benign

1.0

Varity_R

0.049

gMVP

0.32

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over