rs977500969

Variant names:

• chr9-3932370-G-C
• rs977500969
• NM_001042413.2:c.1973C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001042413.2(GLIS3):​c.1973C>G​(p.Ala658Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A658E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.27
• 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: Ambry Genetics, Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Tourette syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23424765).
• BP6: Variant 9-3932370-G-C is Benign according to our data. Variant chr9-3932370-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 549529.

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.1973C>G	p.Ala658Gly	missense	Exon 6 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.1973C>G	p.Ala658Gly	missense	Exon 6 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1973C>G	p.Ala658Gly	missense	Exon 6 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.1973C>G	p.Ala658Gly	missense	Exon 6 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.1508C>G	p.Ala503Gly	missense	Exon 5 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000467497.6	TSL:1	n.513C>G		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151928 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459710 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726314

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110102

Other (OTH) AF: 0.0000332 AC: 2 AN: 60310

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151928 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74214

African (AFR) AF: 0.00 AC: 0 AN: 41260

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	Monogenic diabetes (1)
-	1	-	Neonatal diabetes mellitus with congenital hypothyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.039
Sift	Benign	0.065	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.31	B
Vest4		0.20
MutPred		0.21		Loss of MoRF binding (P = 0.1188)
MVP		0.60
MPC		0.10
ClinPred		0.78	D
GERP RS		4.0
Varity_R		0.15
gMVP		0.24
Mutation Taster		=84/16	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: rs977500969; hg19: chr9-3932370;