9-4118279-T-C

Variant summary

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

The NM_001042413.2(GLIS3):c.1199A>G(p.His400Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,585,102 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. H400Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.95

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=0.028537512).
• BP6: Variant 9-4118279-T-C is Benign according to our data. Variant chr9-4118279-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549530.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000768 (117/152304) while in subpopulation NFE AF= 0.00146 (99/67992). AF 95% confidence interval is 0.00122. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS3	NM_001042413.2	c.1199A>G	p.His400Arg	missense_variant	4/11	ENST00000381971.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS3	ENST00000381971.8	c.1199A>G	p.His400Arg	missense_variant	4/11	5	NM_001042413.2	P1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000767 AC: 143 AN: 186350 Hom.: 0 AF XY: 0.000837 AC XY: 86 AN XY: 102802

Gnomad AFR exome AF: 0.000408

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000762

Gnomad FIN exome AF: 0.0000634

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.000412

GnomAD4 exome AF: 0.00150 AC: 2154 AN: 1432798 Hom.: 4 Cov.: 36 AF XY: 0.00144 AC XY: 1026 AN XY: 710478

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.000122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00182

Gnomad4 OTH exome AF: 0.000676

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74482

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000737

ESP6500AA AF: 0.000561 AC: 2

ESP6500EA AF: 0.000568 AC: 4

ExAC AF: 0.000625 AC: 72

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 245 of the GLIS3 protein (p.His245Arg). This variant is present in population databases (rs376031632, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with GLIS3-related conditions. ClinVar contains an entry for this variant (Variation ID: 549530). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neonatal diabetes mellitus with congenital hypothyroidism Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

May 22, 2017

ACMG Criteria:PP3 (3 predictors), BP4 (7 predictors), BP5 (alternate cause) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.055	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.020
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.73	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.078
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.18	T;T
Polyphen		0.18	B;B
Vest4		0.29
MVP		0.62
MPC		0.22
ClinPred		0.059	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.29

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: rs376031632; hg19: chr9-4118279;