rs10116901

Positions:

• chr9-3826440-T-C
• chr9-3826440-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001042413.2(GLIS3):​c.*1832A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0944 in 142,114 control chromosomes in the GnomAD database, including 804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.094 (804 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: GLIS3 NM_001042413.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-3826440-T-C is Benign according to our data. Variant chr9-3826440-T-C is described in ClinVar as [Benign]. Clinvar id is 366925.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS3	NM_001042413.2	c.*1832A>G		3_prime_UTR_variant	11/11	ENST00000381971.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS3	ENST00000381971.8	c.*1832A>G		3_prime_UTR_variant	11/11	5	NM_001042413.2	P1

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 13381 AN: 142000 Hom.: 802 Cov.: 33

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0654

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.000644

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0592

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.0799

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

GnomAD4 genome AF: 0.0944 AC: 13409 AN: 142114 Hom.: 804 Cov.: 33 AF XY: 0.0935 AC XY: 6421 AN XY: 68644

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.000645

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.0763

Gnomad4 NFE AF: 0.0681

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0114 Hom.: 274

Bravo AF: 0.0924

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal diabetes mellitus with congenital hypothyroidism Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.24
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10116901; hg19: chr9-3826440;