chr9-4118324-C-T

Variant names:

• chr9-4118324-C-T
• rs200959196
• NM_001042413.2:c.1154G>A

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.1154G>A​(p.Gly385Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,058 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G385S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.450
• 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=0.058768123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2	c.1154G>A	p.Gly385Asp	missense_variant	Exon 4 of 11	ENST00000381971.8	NP_001035878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS3	ENST00000381971.8	c.1154G>A	p.Gly385Asp	missense_variant	Exon 4 of 11	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422058 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 704866

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000307 AC: 1 AN: 32606

American (AMR) AF: 0.00 AC: 0 AN: 39646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.00 AC: 0 AN: 37634

South Asian (SAS) AF: 0.00 AC: 0 AN: 82866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095128

Other (OTH) AF: 0.00 AC: 0 AN: 58918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.9
DANN	Benign	0.58
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		-0.45
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.042
Sift	Benign	0.28	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.36		Gain of solvent accessibility (P = 0.0354);.;
MVP		0.44
MPC		0.030
ClinPred		0.062	T
GERP RS		2.4
Varity_R		0.056
gMVP		0.50
Mutation Taster		=95/5	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: rs200959196; hg19: chr9-4118324;