dbSNP rs140378060: GLUL:c.603+5G>A (chr1-182385755-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001033044.4(GLUL):c.603+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,614,072 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 21 hom. )

Consequence

GLUL
NM_001033044.4 splice_region, intron

Scores

Splicing: ADA: 0.06266

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.48

Publications

1 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, 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

GLUL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-182385755-C-T is Benign according to our data. Variant chr1-182385755-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 293945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00334 (509/152268) while in subpopulation NFE AF = 0.00529 (360/68016). AF 95% confidence interval is 0.00484. There are 2 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLUL	NM_001033044.4	MANE Select	c.603+5G>A	splice_region intron	N/A	NP_001028216.1	P15104
GLUL	NM_001033056.4		c.603+5G>A	splice_region intron	N/A	NP_001028228.1	P15104
GLUL	NM_002065.7		c.603+5G>A	splice_region intron	N/A	NP_002056.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLUL	ENST00000331872.11	TSL:1 MANE Select	c.603+5G>A	splice_region intron	N/A	ENSP00000356537.6	P15104
GLUL	ENST00000339526.9	TSL:1	c.1005+5G>A	splice_region intron	N/A	ENSP00000344958.5	A0ABJ7BD24
GLUL	ENST00000311223.9	TSL:1	c.603+5G>A	splice_region intron	N/A	ENSP00000307900.5	P15104

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00529

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00375

AC:

943

AN:

251426

AF XY:

0.00400

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00494

Gnomad ASJ exome

AF:

0.00446

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00517

Gnomad OTH exome

AF:

0.00733

GnomAD4 exome

AF:

0.00420

AC:

6142

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

3056

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33478

American (AMR)

AF:

0.00505

AC:

226

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00179

AC:

154

AN:

86258

European-Finnish (FIN)

AF:

0.00200

AC:

107

AN:

53420

Middle Eastern (MID)

AF:

0.00732

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00473

AC:

5265

AN:

1111964

Other (OTH)

AF:

0.00384

AC:

232

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

359

718

1077

1436

1795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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

AF:

0.00334

AC:

509

AN:

152268

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

246

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41552

American (AMR)

AF:

0.00425

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00529

AC:

360

AN:

68016

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00424

Hom.:

Bravo

AF:

0.00358

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00616

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital brain dysgenesis due to glutamine synthetase deficiency (2)

not provided (2)

GLUL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.12

(source)

DANN

Benign

0.71

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.063

dbscSNV1_RF

Benign

0.31

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over