chr9-4118208-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042413.2(GLIS3):c.1270T>C(p.Ser424Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,585,008 control chromosomes in the GnomAD database, including 792,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S424L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 1.0 ( 76007 hom., cov: 34)

Exomes 𝑓: 1.0 ( 716201 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.854

Publications

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

GLIS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=7.210914E-7).

BP6

Variant 9-4118208-A-G is Benign according to our data. Variant chr9-4118208-A-G is described in ClinVar as Benign. ClinVar VariationId is 129159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLIS3	NM_001042413.2	MANE Select	c.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	NP_001035878.1	Q8NEA6-2
GLIS3	NM_001438906.1		c.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	NP_001425835.1
GLIS3	NM_001438907.1		c.1270T>C	p.Ser424Pro	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.1270T>C	p.Ser424Pro	missense	Exon 4 of 11	ENSP00000371398.3	Q8NEA6-2
GLIS3	ENST00000324333.14	TSL:1	c.805T>C	p.Ser269Pro	missense	Exon 3 of 10	ENSP00000325494.10	Q8NEA6-1
GLIS3	ENST00000491889.6	TSL:1	n.*633T>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1	F8WEV9

Frequencies

GnomAD3 genomes

AF:

0.999

AC:

152053

AN:

152208

Hom.:

75949

Cov.:

show subpopulations

Gnomad AFR

AF:

0.996

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

1.00

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

1.00

GnomAD2 exomes

AF:

1.00

AC:

202267

AN:

202322

AF XY:

1.00

show subpopulations

Gnomad AFR exome

AF:

0.996

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

AF:

1.00

AC:

1432543

AN:

1432684

Hom.:

716201

Cov.:

AF XY:

1.00

AC XY:

709304

AN XY:

709358

show subpopulations

African (AFR)

AF:

0.996

AC:

32833

AN:

32952

American (AMR)

AF:

1.00

AC:

41887

AN:

41892

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

24802

AN:

24802

East Asian (EAS)

AF:

1.00

AC:

39016

AN:

39016

South Asian (SAS)

AF:

1.00

AC:

82190

AN:

82190

European-Finnish (FIN)

AF:

1.00

AC:

49809

AN:

49810

Middle Eastern (MID)

AF:

1.00

AC:

5462

AN:

5462

European-Non Finnish (NFE)

AF:

1.00

AC:

1097583

AN:

1097590

Other (OTH)

AF:

1.00

AC:

58961

AN:

58970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21588

43176

64764

86352

107940

<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:

0.999

AC:

152169

AN:

152324

Hom.:

76007

Cov.:

AF XY:

0.999

AC XY:

74404

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.996

AC:

41437

AN:

41590

American (AMR)

AF:

1.00

AC:

15309

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5156

AN:

5156

South Asian (SAS)

AF:

1.00

AC:

4834

AN:

4834

European-Finnish (FIN)

AF:

1.00

AC:

10628

AN:

10628

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68014

AN:

68014

Other (OTH)

AF:

1.00

AC:

2113

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.999

Hom.:

28119

Bravo

AF:

0.999

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.996

AC:

3063

ESP6500EA

AF:

1.00

AC:

6261

ExAC

AF:

0.999

AC:

113004

Asia WGS

AF:

0.999

AC:

3470

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Neonatal diabetes mellitus with congenital hypothyroidism (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.049

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.14

MetaRNN

Benign

7.2e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.42

PhyloP100

-0.85

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.42

REVEL

Benign

0.0030

Sift

Benign

0.65

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.058

MPC

0.029

ClinPred

0.00091

GERP RS

-2.6

Varity_R

0.043

gMVP

0.18

Mutation Taster

=99/1

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

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