rs76094493

Variant names:

• chr9-3828379-G-A
• rs76094493
• NM_001042413.2:c.2686C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-3828379-G-A
• chr9-3828379-G-T

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.2686C>T​(p.Leu896Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,613,564 control chromosomes in the GnomAD database, including 630 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L896L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (360 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (270 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.633
• Publications: 6 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=0.0016325116).
• BP6: Variant 9-3828379-G-A is Benign according to our data. Variant chr9-3828379-G-A is described in ClinVar as Benign. ClinVar VariationId is 129155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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.2686C>T	p.Leu896Phe	missense	Exon 11 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.2686C>T	p.Leu896Phe	missense	Exon 11 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.2686C>T	p.Leu896Phe	missense	Exon 11 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.2686C>T	p.Leu896Phe	missense	Exon 11 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.2221C>T	p.Leu741Phe	missense	Exon 10 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000491889.6	TSL:1	n.*2049C>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000419914.1	F8WEV9

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5500 AN: 152148 Hom.: 360 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.00919 AC: 2300 AN: 250170 AF XY: 0.00634

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00353 AC: 5155 AN: 1461298 Hom.: 270 Cov.: 31 AF XY: 0.00300 AC XY: 2179 AN XY: 726940

African (AFR) AF: 0.125 AC: 4192 AN: 33462

American (AMR) AF: 0.00622 AC: 278 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00225 AC: 12 AN: 5332

European-Non Finnish (NFE) AF: 0.000185 AC: 206 AN: 1111994

Other (OTH) AF: 0.00744 AC: 449 AN: 60350

GnomAD4 genome AF: 0.0362 AC: 5507 AN: 152266 Hom.: 360 Cov.: 33 AF XY: 0.0339 AC XY: 2527 AN XY: 74462

African (AFR) AF: 0.126 AC: 5236 AN: 41508

American (AMR) AF: 0.0124 AC: 189 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68032

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.0117 Hom.: 366

Bravo AF: 0.0403

ESP6500AA AF: 0.122 AC: 539

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0113 AC: 1376

Asia WGS AF: 0.00636 AC: 22 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	GLIS3-related disorder (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Neonatal diabetes mellitus with congenital hypothyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.0038
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.63
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.045
Sift	Benign	0.21	T
Sift4G	Benign	0.35	T
Polyphen		0.88	P
Vest4		0.071
MPC		0.22
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.090
gMVP		0.13
Mutation Taster		=99/1	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: rs76094493; hg19: chr9-3828379; COSMIC: COSV60930913;