rs1057520087

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001033044.4(GLUL):c.515G>C(p.Gly172Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G172S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GLUL
NM_001033044.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.54

Publications

0 publications found

Variant links:

Genes affected

GLUL (HGNC:4341): (glutamate-ammonia ligase) The protein encoded by this gene belongs to the glutamine synthetase family. It catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. This protein plays a role in ammonia and glutamate detoxification, acid-base homeostasis, cell signaling, and cell proliferation. Glutamine is an abundant amino acid, and is important to the biosynthesis of several amino acids, pyrimidines, and purines. Mutations in this gene are associated with congenital glutamine deficiency, and overexpression of this gene was observed in some primary liver cancer samples. There are six pseudogenes of this gene found on chromosomes 2, 5, 9, 11, and 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

GLUL Gene-Disease associations (from GenCC):

congenital brain dysgenesis due to glutamine synthetase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
developmental and epileptic encephalopathy 116
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

GLUL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUL	NM_001033044.4 link	c.515G>C	p.Gly172Ala	missense_variant	Exon 5 of 7	ENST00000331872.11	NP_001028216.1	P15104A8YXX4
GLUL	NM_001033056.4 link	c.515G>C	p.Gly172Ala	missense_variant	Exon 5 of 7		NP_001028228.1	P15104A8YXX4
GLUL	NM_002065.7 link	c.515G>C	p.Gly172Ala	missense_variant	Exon 6 of 8		NP_002056.2	P15104A8YXX4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUL	ENST00000331872.11 link	c.515G>C	p.Gly172Ala	missense_variant	Exon 5 of 7	1	NM_001033044.4	ENSP00000356537.6		P15104

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251270

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461378

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111540

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.515G>C (p.G172A) alteration is located in exon 6 (coding exon 4) of the GLUL gene. This alteration results from a G to C substitution at nucleotide position 515, causing the glycine (G) at amino acid position 172 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D;D;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;.;.

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.8

.;L;L;L;L

PhyloP100

7.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.1

.;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Benign

0.32

.;T;T;T;T

Sift4G

Benign

0.19

.;T;T;T;T

Polyphen

0.99

.;D;D;D;D

Vest4

0.93

MutPred

0.70

.;Loss of stability (P = 0.0621);Loss of stability (P = 0.0621);Loss of stability (P = 0.0621);Loss of stability (P = 0.0621);

MVP

0.92

MPC

1.4

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.95

Mutation Taster

=35/65

disease causing

(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