chr9-4118215-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001042413.2(GLIS3):​c.1263C>G​(p.Asp421Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D421D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.535
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061327547).

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>G	p.Asp421Glu	missense	Exon 4 of 11	NP_001035878.1
	GLIS3	NM_001438906.1		c.1263C>G	p.Asp421Glu	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1263C>G	p.Asp421Glu	missense	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>G	p.Asp421Glu	missense	Exon 4 of 11	ENSP00000371398.3
	GLIS3	ENST00000324333.14	TSL:1	c.798C>G	p.Asp266Glu	missense	Exon 3 of 10	ENSP00000325494.10
	GLIS3	ENST00000491889.6	TSL:1	n.*626C>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432316 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 709310

African (AFR) AF: 0.00 AC: 0 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: 49452

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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0050
DANN	Benign	0.85
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.36	N
PhyloP100		-0.54
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.077
Sift	Benign	0.23	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.061
MutPred		0.29		Gain of phosphorylation at S269 (P = 0.1755)
MVP		0.39
MPC		0.025
ClinPred		0.091	T
GERP RS		-4.5
Varity_R		0.037
gMVP		0.094
Mutation Taster		=91/9	polymorphism

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;