dbSNP rs982751743: GLIS1:p.Gly630Ala (chr1-53510022-C-G) – 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_001367484.1(GLIS1):c.1889G>C(p.Gly630Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G630E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GLIS1
NM_001367484.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68

Publications

0 publications found

Variant links:

Genes affected

GLIS1 (HGNC:29525): (GLIS family zinc finger 1) GLIS1 is a GLI (MIM 165220)-related Kruppel-like zinc finger protein that functions as an activator and repressor of transcription (Kim et al., 2002 [PubMed 12042312]).[supplied by OMIM, Mar 2008]

GLIS1 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=0.06063077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLIS1	NM_001367484.1 link	c.1889G>C	p.Gly630Ala	missense_variant	Exon 9 of 11	ENST00000628545.2	NP_001354413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLIS1	ENST00000628545.2 link	c.1889G>C	p.Gly630Ala	missense_variant	Exon 9 of 11	5	NM_001367484.1	ENSP00000486112.1		A0A0D9SEX9
GLIS1	ENST00000312233.4 link	c.1364G>C	p.Gly455Ala	missense_variant	Exon 8 of 10	2		ENSP00000309653.2		Q8NBF1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1115020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

528654

African (AFR)

AF:

0.00

AC:

AN:

24086

American (AMR)

AF:

0.00

AC:

AN:

10516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14592

East Asian (EAS)

AF:

0.00

AC:

AN:

28390

South Asian (SAS)

AF:

0.00

AC:

AN:

21204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3912

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

930468

Other (OTH)

AF:

0.00

AC:

AN:

44580

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1364G>C (p.G455A) alteration is located in exon 8 (coding exon 6) of the GLIS1 gene. This alteration results from a G to C substitution at nucleotide position 1364, causing the glycine (G) at amino acid position 455 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.024

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

L;.

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

0.47

N;.

REVEL

Benign

0.033

Sift

Benign

0.51

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.060

B;.

Vest4

0.15

MutPred

0.11

Loss of catalytic residue at G455 (P = 0.0996);.;

MVP

0.33

MPC

0.17

ClinPred

0.11

GERP RS

3.4

Varity_R

0.046

gMVP

0.31

Mutation Taster

=90/10

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over