chr9-4117933-C-G

Variant names:

• chr9-4117933-C-G
• rs72687988
• NM_001042413.2:c.1545G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001042413.2(GLIS3):​c.1545G>C​(p.Glu515Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,172 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (12 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.34
• Publications: 12 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007063985).
• BP6: Variant 9-4117933-C-G is Benign according to our data. Variant chr9-4117933-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 196581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

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.1545G>C	p.Glu515Asp	missense	Exon 4 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.1545G>C	p.Glu515Asp	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1545G>C	p.Glu515Asp	missense	Exon 4 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.1545G>C	p.Glu515Asp	missense	Exon 4 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.1080G>C	p.Glu360Asp	missense	Exon 3 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000467497.6	TSL:1	n.85G>C		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152202 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00291 AC: 732 AN: 251376 AF XY: 0.00285

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00432

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00407 AC: 5944 AN: 1461852 Hom.: 12 Cov.: 38 AF XY: 0.00406 AC XY: 2949 AN XY: 727226

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00210 AC: 94 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86258

European-Finnish (FIN) AF: 0.00111 AC: 59 AN: 53382

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5768

European-Non Finnish (NFE) AF: 0.00468 AC: 5203 AN: 1112008

Other (OTH) AF: 0.00394 AC: 238 AN: 60396

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152320 Hom.: 2 Cov.: 31 AF XY: 0.00283 AC XY: 211 AN XY: 74486

African (AFR) AF: 0.000914 AC: 38 AN: 41580

American (AMR) AF: 0.00307 AC: 47 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00486 Hom.: 3

Bravo AF: 0.00326

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	not specified (3)
-	-	1	Neonatal diabetes mellitus with congenital hypothyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.097
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.41	N
PhyloP100		3.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.38	T
Sift4G	Benign	0.32	T
Polyphen		0.010	B
Vest4		0.28
MutPred		0.40		Gain of phosphorylation at Y356 (P = 0.144)
MVP		0.94
MPC		0.15
ClinPred		0.010	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.31
Mutation Taster		=90/10	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: rs72687988; hg19: chr9-4117933; COSMIC: COSV60924965; COSMIC: COSV60924965;