Genetic Variant NM_001042413.2:c.1270T>G (chr9-4118208-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001042413.2(GLIS3):c.1270T>G(p.Ser424Ala) 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 1,432,684 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. S424P) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GLIS3
NM_001042413.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.854

Publications

0 publications found

Variant links:

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)

GLIS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.029227346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS3	NM_001042413.2 link	c.1270T>G	p.Ser424Ala	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 link	c.1270T>G	p.Ser424Ala	missense_variant	Exon 4 of 11	5	NM_001042413.2	ENSP00000371398.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32952

American (AMR)

AF:

0.00

AC:

AN:

41892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24802

East Asian (EAS)

AF:

0.00

AC:

AN:

39016

South Asian (SAS)

AF:

0.00

AC:

AN:

82190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097590

Other (OTH)

AF:

0.00

AC:

AN:

58970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.21

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.097

T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

L;.

PhyloP100

-0.85

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.0050

Sift

Benign

0.60

T;T

Sift4G

Benign

0.79

T;T

Polyphen

0.0

B;B

Vest4

0.063

MutPred

0.25

Loss of phosphorylation at S269 (P = 0.0538);.;

MVP

0.27

MPC

0.024

ClinPred

0.018

GERP RS

-2.6

Varity_R

0.039

gMVP

0.14

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over