1-182381774-C-T

Position:

• chr1-182381774-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001033044.4(GLUL):​c.*2631G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,046 control chromosomes in the GnomAD database, including 2,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2411 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: GLUL NM_001033044.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.35

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-182381774-C-T is Benign according to our data. Variant chr1-182381774-C-T is described in ClinVar as [Benign]. Clinvar id is 293884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLUL	NM_001033044.4	c.*2631G>A		3_prime_UTR_variant	7/7	ENST00000331872.11
GLUL	NM_001033056.4	c.*2631G>A		3_prime_UTR_variant	7/7
GLUL	NM_002065.7	c.*2631G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLUL	ENST00000331872.11	c.*2631G>A		3_prime_UTR_variant	7/7	1	NM_001033044.4	P1
GLUL	ENST00000311223.9	c.*2631G>A		3_prime_UTR_variant	8/8	1		P1
GLUL	ENST00000417584.6	c.*2631G>A		3_prime_UTR_variant	7/7	5		P1
GLUL	ENST00000642379.1	c.*2631G>A		3_prime_UTR_variant	8/8

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24018 AN: 151902 Hom.: 2414 Cov.: 32

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.115 AC: 3 AN: 26 Hom.: 1 Cov.: 0 AF XY: 0.115 AC XY: 3 AN XY: 26

Gnomad4 NFE exome AF: 0.115

GnomAD4 genome AF: 0.158 AC: 24008 AN: 152020 Hom.: 2411 Cov.: 32 AF XY: 0.163 AC XY: 12125 AN XY: 74276

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.179

Alfa AF: 0.0836 Hom.: 127

Bravo AF: 0.154

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital brain dysgenesis due to glutamine synthetase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.66
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2296522; hg19: chr1-182350909;