rs138497710

chr9-4118287-C-Gchr9-4118287-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 393416.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr9-4118287-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00173 (264/152324) while in subpopulation NFE AF= 0.0026 (177/68008). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS3	NM_001042413.2	c.1191G>C	p.Gln397His	missense_variant	4/11	ENST00000381971.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS3	ENST00000381971.8	c.1191G>C	p.Gln397His	missense_variant	4/11	5	NM_001042413.2	P1

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

GnomAD3 exomes AF: 0.00222 AC: 411 AN: 185294 Hom.: 0 AF XY: 0.00214 AC XY: 219 AN XY: 102236

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 SAS exome AF: 0.000152

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

Gnomad4 AFR exome AF: 0.000334

Gnomad4 AMR exome AF: 0.000685

Gnomad4 ASJ exome AF: 0.00557

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000157

Gnomad4 FIN exome AF: 0.00308

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00225

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

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00189

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 07, 2016

ACMG Criteria: PP3, BP4 -

GLIS3-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neonatal diabetes mellitus with congenital hypothyroidism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0095	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.058
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.49	P;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

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

LitVar

Other links and lift over

dbSNP: rs138497710; hg19: chr9-4118287;