NM_001042413.2:c.1126C>T

Variant names:

• chr9-4118352-G-A
• rs76342955
• NM_001042413.2:c.1126C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001042413.2(GLIS3):​c.1126C>T​(p.Pro376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,583,854 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (12 hom.)
• Consequence: GLIS3 NM_001042413.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.379
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025414526).
• BP6: Variant 9-4118352-G-A is Benign according to our data. Variant chr9-4118352-G-A is described in ClinVar as Benign. ClinVar VariationId is 366984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00754 (1148/152332) while in subpopulation AFR AF = 0.0262 (1090/41588). AF 95% confidence interval is 0.0249. There are 9 homozygotes in GnomAd4. There are 538 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1126C>T	p.Pro376Ser	missense	Exon 4 of 11	NP_001035878.1	Q8NEA6-2
	GLIS3	NM_001438906.1		c.1126C>T	p.Pro376Ser	missense	Exon 4 of 11	NP_001425835.1
	GLIS3	NM_001438907.1		c.1126C>T	p.Pro376Ser	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.1126C>T	p.Pro376Ser	missense	Exon 4 of 11	ENSP00000371398.3	Q8NEA6-2
	GLIS3	ENST00000324333.14	TSL:1	c.661C>T	p.Pro221Ser	missense	Exon 3 of 10	ENSP00000325494.10	Q8NEA6-1
	GLIS3	ENST00000491889.6	TSL:1	n.*489C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000419914.1	F8WEV9

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1142 AN: 152214 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00154 AC: 296 AN: 192246 AF XY: 0.00122

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000241

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000748 AC: 1071 AN: 1431522 Hom.: 12 Cov.: 36 AF XY: 0.000635 AC XY: 451 AN XY: 710698

African (AFR) AF: 0.0273 AC: 893 AN: 32768

American (AMR) AF: 0.00155 AC: 64 AN: 41206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 38176

South Asian (SAS) AF: 0.0000476 AC: 4 AN: 84074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43768

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5678

European-Non Finnish (NFE) AF: 0.00000999 AC: 11 AN: 1100748

Other (OTH) AF: 0.00162 AC: 96 AN: 59414

GnomAD4 genome AF: 0.00754 AC: 1148 AN: 152332 Hom.: 9 Cov.: 32 AF XY: 0.00722 AC XY: 538 AN XY: 74484

African (AFR) AF: 0.0262 AC: 1090 AN: 41588

American (AMR) AF: 0.00268 AC: 41 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00404 Hom.: 1

Bravo AF: 0.00842

ESP6500AA AF: 0.0168 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00168 AC: 193

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Monogenic diabetes (1)
-	-	1	Neonatal diabetes mellitus with congenital hypothyroidism (1)
-	-	1	Transitory neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.59
DANN	Benign	0.38
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.63	N
PhyloP100		0.38
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.023
Sift	Benign	0.53	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.057
MVP		0.27
MPC		0.026
ClinPred		0.00084	T
GERP RS		-3.4
Varity_R		0.025
gMVP		0.23
Mutation Taster		=99/1	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: rs76342955; hg19: chr9-4118352; COSMIC: COSV60930778; COSMIC: COSV60930778;