chr9-4118215-G-A

Variant names:

• chr9-4118215-G-A
• rs755713904
• NM_001042413.2:c.1263C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001042413.2(GLIS3):​c.1263C>T​(p.Asp421Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,584,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLIS3 NM_001042413.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.535
• Publications: 1 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-4118215-G-A is Benign according to our data. Variant chr9-4118215-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 435336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.535 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS3	NM_001042413.2	MANE Select	c.1263C>T	p.Asp421Asp	synonymous	Exon 4 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.1263C>T	p.Asp421Asp	synonymous	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1263C>T	p.Asp421Asp	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.1263C>T	p.Asp421Asp	synonymous	Exon 4 of 11	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.798C>T	p.Asp266Asp	synonymous	Exon 3 of 10	ENSP00000325494.10
	GLIS3	ENST00000491889.6	TSL:1	n.*626C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000512 AC: 1 AN: 195226 AF XY: 0.00

Gnomad AFR exome AF: 0.0000938

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1432314 Hom.: 0 Cov.: 36 AF XY: 0.00000141 AC XY: 1 AN XY: 709308

African (AFR) AF: 0.0000606 AC: 2 AN: 33002

American (AMR) AF: 0.00 AC: 0 AN: 41768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24896

East Asian (EAS) AF: 0.00 AC: 0 AN: 38882

South Asian (SAS) AF: 0.00 AC: 0 AN: 82242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097580

Other (OTH) AF: 0.00 AC: 0 AN: 59008

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000965 AC: 4 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.012
DANN	Benign	0.59
PhyloP100		-0.54

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: rs755713904; hg19: chr9-4118215;