NM_001042413.2:c.1191G>C

Variant names:

• chr9-4118287-C-G
• rs138497710
• NM_001042413.2:c.1191G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001042413.2(GLIS3):​c.1191G>C​(p.Gln397His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,583,390 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q397R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.33
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009463966).
• BP6: Variant 9-4118287-C-G is Benign according to our data. Variant chr9-4118287-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393416.
• BS2: High Homozygotes in GnomAdExome4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.1191G>C	p.Gln397His	missense	Exon 4 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.1191G>C	p.Gln397His	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1191G>C	p.Gln397His	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.1191G>C	p.Gln397His	missense	Exon 4 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.726G>C	p.Gln242His	missense	Exon 3 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000491889.6	TSL:1	n.*554G>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1	F8WEV9

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00222 AC: 411 AN: 185294 AF XY: 0.00214

Gnomad AFR exome AF: 0.000512

Gnomad AMR exome AF: 0.000679

Gnomad ASJ exome AF: 0.00551

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00332

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00186

GnomAD4 exome AF: 0.00304 AC: 4352 AN: 1431066 Hom.: 9 Cov.: 36 AF XY: 0.00296 AC XY: 2103 AN XY: 709550

African (AFR) AF: 0.000334 AC: 11 AN: 32980

American (AMR) AF: 0.000685 AC: 28 AN: 40870

Ashkenazi Jewish (ASJ) AF: 0.00557 AC: 142 AN: 25502

East Asian (EAS) AF: 0.00 AC: 0 AN: 38342

South Asian (SAS) AF: 0.000157 AC: 13 AN: 82954

European-Finnish (FIN) AF: 0.00308 AC: 146 AN: 47478

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5606

European-Non Finnish (NFE) AF: 0.00353 AC: 3878 AN: 1098178

Other (OTH) AF: 0.00225 AC: 133 AN: 59156

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74482

African (AFR) AF: 0.000433 AC: 18 AN: 41588

American (AMR) AF: 0.000523 AC: 8 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00260 AC: 177 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00147

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000990 AC: 7

ExAC AF: 0.00192 AC: 221

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (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	0.19
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.058
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.17	T
Polyphen		0.49	P
Vest4		0.57
MutPred		0.28		Loss of solvent accessibility (P = 0.1922)
MVP		0.76
MPC		0.21
ClinPred		0.024	T
GERP RS		4.7
Varity_R		0.30
gMVP		0.49
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: rs138497710; hg19: chr9-4118287;