chr1-182385848-C-G

Variant names:

• chr1-182385848-C-G
• rs1057520087
• NM_001033044.4:c.515G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

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, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• developmental and epileptic encephalopathy 116

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033044.4. 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
	GLUL	NM_001033044.4	MANE Select	c.515G>C	p.Gly172Ala	missense	Exon 5 of 7	NP_001028216.1	P15104
	GLUL	NM_001033056.4		c.515G>C	p.Gly172Ala	missense	Exon 5 of 7	NP_001028228.1	P15104
	GLUL	NM_002065.7		c.515G>C	p.Gly172Ala	missense	Exon 6 of 8	NP_002056.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUL	ENST00000331872.11	TSL:1 MANE Select	c.515G>C	p.Gly172Ala	missense	Exon 5 of 7	ENSP00000356537.6	P15104
	GLUL	ENST00000339526.9	TSL:1	c.917G>C	p.Gly306Ala	missense	Exon 5 of 7	ENSP00000344958.5	A0ABJ7BD24
	GLUL	ENST00000311223.9	TSL:1	c.515G>C	p.Gly172Ala	missense	Exon 6 of 8	ENSP00000307900.5	P15104

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251270 AF XY: 0.00000736

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: 1 AN: 1461378 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111540

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.86
Sift	Benign	0.32	T
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.93
MutPred		0.70		Loss of stability (P = 0.0621)
MVP		0.92
MPC		1.4
ClinPred		0.99	D
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

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: rs1057520087; hg19: chr1-182354983;