rs66766243

Variant names:

• chr9-3824934-AAT-A
• rs66766243
• NM_001042413.2:c.*3336_*3337delAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001042413.2(GLIS3):​c.*3336_*3337delAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 123,496 control chromosomes in the GnomAD database, including 16,835 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (16833 hom., cov: 0)
  • Exomes 𝑓: 0.38 (2 hom.)
• Consequence: GLIS3 NM_001042413.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.652
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P, Ambry Genetics
• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 9-3824934-AAT-A is Benign according to our data. Variant chr9-3824934-AAT-A is described in ClinVar as Benign. ClinVar VariationId is 366891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

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.*3336_*3337delAT		3_prime_UTR	Exon 11 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.*3336_*3337delAT		3_prime_UTR	Exon 11 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.*3336_*3337delAT		3_prime_UTR	Exon 11 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.*3336_*3337delAT		3_prime_UTR	Exon 11 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.*3336_*3337delAT		3_prime_UTR	Exon 10 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000491889.6	TSL:1	n.*5492_*5493delAT		non_coding_transcript_exon	Exon 10 of 10	ENSP00000419914.1	F8WEV9

Frequencies

GnomAD3 genomes AF: 0.535 AC: 66065 AN: 123470 Hom.: 16829 Cov.: 0

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.464

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.549

GnomAD4 exome AF: 0.375 AC: 9 AN: 24 Hom.: 2 AF XY: 0.500 AC XY: 7 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.375 AC: 9 AN: 24

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.535 AC: 66065 AN: 123472 Hom.: 16833 Cov.: 0 AF XY: 0.536 AC XY: 31623 AN XY: 59024

African (AFR) AF: 0.397 AC: 12099 AN: 30502

American (AMR) AF: 0.570 AC: 7187 AN: 12598

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1592 AN: 3078

East Asian (EAS) AF: 0.640 AC: 2961 AN: 4626

South Asian (SAS) AF: 0.639 AC: 2663 AN: 4166

European-Finnish (FIN) AF: 0.576 AC: 3419 AN: 5934

Middle Eastern (MID) AF: 0.453 AC: 105 AN: 232

European-Non Finnish (NFE) AF: 0.578 AC: 34587 AN: 59828

Other (OTH) AF: 0.552 AC: 932 AN: 1688

Alfa AF: 0.386 Hom.: 114

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	Neonatal diabetes mellitus with congenital hypothyroidism (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs66766243; hg19: chr9-3824934; COSMIC: COSV60933117; COSMIC: COSV60933117;