9-3824933-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001042413.2(GLIS3):c.*3339T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 118,592 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLIS3 NM_001042413.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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 (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00189 (224/118592) while in subpopulation AMR AF= 0.0033 (36/10912). AF 95% confidence interval is 0.00245. There are 2 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS3	NM_001042413.2	c.*3339T>A		3_prime_UTR_variant	11/11	ENST00000381971.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS3	ENST00000381971.8	c.*3339T>A		3_prime_UTR_variant	11/11	5	NM_001042413.2	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 222 AN: 118532 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.000565

Gnomad AMI AF: 0.00382

Gnomad AMR AF: 0.00330

Gnomad ASJ AF: 0.00139

Gnomad EAS AF: 0.00200

Gnomad SAS AF: 0.00295

Gnomad FIN AF: 0.000917

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00236

Gnomad OTH AF: 0.00462

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 32 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.00189 AC: 224 AN: 118592 Hom.: 2 Cov.: 29 AF XY: 0.00199 AC XY: 113 AN XY: 56738

Gnomad4 AFR AF: 0.000594

Gnomad4 AMR AF: 0.00330

Gnomad4 ASJ AF: 0.00139

Gnomad4 EAS AF: 0.00201

Gnomad4 SAS AF: 0.00294

Gnomad4 FIN AF: 0.000917

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00459

Alfa AF: 0.000927 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	3.3
Dann	Benign	0.60

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs868836548; hg19: chr9-3824933;