rs6415788

Variant names:

• chr9-4118111-G-T
• rs6415788
• NM_001042413.2:c.1367C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-4118111-G-T
• chr9-4118111-G-A
• chr9-4118111-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042413.2(GLIS3):​c.1367C>A​(p.Pro456Gln) variant causes a missense change. The variant allele was found at a frequency of 0.614 in 1,527,248 control chromosomes in the GnomAD database, including 289,946 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P456P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.62 (29037 hom., cov: 27)
  • Exomes 𝑓: 0.61 (260909 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.11
• Publications: 37 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.9029145E-7).
• BP6: Variant 9-4118111-G-T is Benign according to our data. Variant chr9-4118111-G-T is described in ClinVar as Benign. ClinVar VariationId is 129160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 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.1367C>A	p.Pro456Gln	missense	Exon 4 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.1367C>A	p.Pro456Gln	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1367C>A	p.Pro456Gln	missense	Exon 4 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.1367C>A	p.Pro456Gln	missense	Exon 4 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.902C>A	p.Pro301Gln	missense	Exon 3 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000491889.6	TSL:1	n.*730C>A		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1	F8WEV9

Frequencies

GnomAD3 genomes AF: 0.623 AC: 92567 AN: 148672 Hom.: 29006 Cov.: 27

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.631

GnomAD2 exomes AF: 0.670 AC: 118472 AN: 176820 AF XY: 0.658

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.815

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.876

Gnomad FIN exome AF: 0.681

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.656

GnomAD4 exome AF: 0.613 AC: 844347 AN: 1378470 Hom.: 260909 Cov.: 39 AF XY: 0.611 AC XY: 413524 AN XY: 677288

African (AFR) AF: 0.604 AC: 18934 AN: 31330

American (AMR) AF: 0.797 AC: 28044 AN: 35168

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 12942 AN: 21302

East Asian (EAS) AF: 0.870 AC: 33603 AN: 38612

South Asian (SAS) AF: 0.549 AC: 40898 AN: 74436

European-Finnish (FIN) AF: 0.663 AC: 31193 AN: 47036

Middle Eastern (MID) AF: 0.618 AC: 3210 AN: 5192

European-Non Finnish (NFE) AF: 0.599 AC: 640011 AN: 1068686

Other (OTH) AF: 0.626 AC: 35512 AN: 56708

GnomAD4 genome AF: 0.623 AC: 92653 AN: 148778 Hom.: 29037 Cov.: 27 AF XY: 0.629 AC XY: 45734 AN XY: 72676

African (AFR) AF: 0.605 AC: 24484 AN: 40464

American (AMR) AF: 0.725 AC: 10863 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2045 AN: 3418

East Asian (EAS) AF: 0.870 AC: 4293 AN: 4934

South Asian (SAS) AF: 0.549 AC: 2586 AN: 4712

European-Finnish (FIN) AF: 0.656 AC: 6730 AN: 10254

Middle Eastern (MID) AF: 0.596 AC: 174 AN: 292

European-Non Finnish (NFE) AF: 0.595 AC: 39761 AN: 66782

Other (OTH) AF: 0.632 AC: 1298 AN: 2054

Alfa AF: 0.607 Hom.: 40396

TwinsUK AF: 0.594 AC: 2202

ALSPAC AF: 0.600 AC: 2312

ESP6500AA AF: 0.686 AC: 2499

ESP6500EA AF: 0.661 AC: 4958

ExAC AF: 0.634 AC: 73042

Asia WGS AF: 0.694 AC: 2415 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Neonatal diabetes mellitus with congenital hypothyroidism (2)
-	-	1	Diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N
PhyloP100		4.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.099
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.19
MPC		0.025
ClinPred		0.0023	T
GERP RS		5.4
Varity_R		0.042
gMVP		0.22
Mutation Taster		=97/3	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: rs6415788; hg19: chr9-4118111; COSMIC: COSV60926763; COSMIC: COSV60926763;