rs74680081

Variant names:

• chr9-4118386-C-A
• rs74680081
• NM_001042413.2:c.1092G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-4118386-C-A
• chr9-4118386-C-G
• chr9-4118386-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The ENST00000381971.8(GLIS3):​c.1092G>T​(p.Pro364Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,600,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P364P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: GLIS3 ENST00000381971.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.57
• Publications: 2 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Tourette syndrome

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-4118386-C-A is Benign according to our data. Variant chr9-4118386-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381971.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.1092G>T	p.Pro364Pro	synonymous	Exon 4 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.1092G>T	p.Pro364Pro	synonymous	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1092G>T	p.Pro364Pro	synonymous	Exon 4 of 11	NP_001425836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	ENST00000381971.8	TSL:5 MANE Select	c.1092G>T	p.Pro364Pro	synonymous	Exon 4 of 11	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.627G>T	p.Pro209Pro	synonymous	Exon 3 of 10	ENSP00000325494.10
	GLIS3	ENST00000491889.6	TSL:1	n.*455G>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000240 AC: 53 AN: 220946 AF XY: 0.000106

Gnomad AFR exome AF: 0.00380

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000203

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000140 AC: 202 AN: 1447724 Hom.: 1 Cov.: 36 AF XY: 0.0000972 AC XY: 70 AN XY: 720088

African (AFR) AF: 0.00517 AC: 172 AN: 33248

American (AMR) AF: 0.000159 AC: 7 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39220

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45246

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108782

Other (OTH) AF: 0.000350 AC: 21 AN: 59960

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74486

African (AFR) AF: 0.00522 AC: 217 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000491 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	GLIS3-related disorder (1)
-	-	1	Neonatal diabetes mellitus with congenital hypothyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.28
DANN	Benign	0.58
PhyloP100		-2.6

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

Other links and lift over

dbSNP: rs74680081; hg19: chr9-4118386;