Genetic Variant AGA:p.Leu105Ile (chr4-177439657-G-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000027.4(AGA):c.313C>A(p.Leu105Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,610,468 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 13 hom., cov: 33)

Exomes 𝑓: 0.010 ( 111 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 9.07

Publications

9 publications found

Variant links:

Genes affected

AGA (HGNC:318): (aspartylglucosaminidase) This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]

AGA Gene-Disease associations (from GenCC):

aspartylglucosaminuria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

AGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000027.4

BP4

Computational evidence support a benign effect (MetaRNN=0.012048036).

BP6

Variant 4-177439657-G-T is Benign according to our data. Variant chr4-177439657-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529230.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 = 0.00854 (1290/150996) while in subpopulation NFE AF = 0.0109 (734/67254). AF 95% confidence interval is 0.0103. There are 13 homozygotes in GnomAd4. There are 718 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGA	NM_000027.4	MANE Select	c.313C>A	p.Leu105Ile	missense	Exon 3 of 9	NP_000018.2
AGA	NM_001171988.2		c.313C>A	p.Leu105Ile	missense	Exon 3 of 9	NP_001165459.1
AGA	NR_033655.2		n.375C>A		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGA	ENST00000264595.7	TSL:1 MANE Select	c.313C>A	p.Leu105Ile	missense	Exon 3 of 9	ENSP00000264595.2
AGA	ENST00000510635.1	TSL:1	c.7C>A	p.Leu3Ile	missense	Exon 1 of 5	ENSP00000421471.1
AGA	ENST00000506853.5	TSL:2	n.347C>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.00855

AC:

1290

AN:

150878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00177

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.00179

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00675

GnomAD2 exomes

AF:

0.00981

AC:

2467

AN:

251432

AF XY:

0.00972

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.0193

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0298

Gnomad NFE exome

AF:

0.0129

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0104

AC:

15123

AN:

1459472

Hom.:

111

Cov.:

AF XY:

0.00997

AC XY:

7237

AN XY:

726122

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33460

American (AMR)

AF:

0.00101

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

513

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00122

AC:

105

AN:

86236

European-Finnish (FIN)

AF:

0.0283

AC:

1510

AN:

53278

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0112

AC:

12449

AN:

1110210

Other (OTH)

AF:

0.00705

AC:

425

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

720

1439

2159

2878

3598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.00854

AC:

1290

AN:

150996

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

718

AN XY:

73858

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41468

American (AMR)

AF:

0.00179

AC:

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0310

AC:

325

AN:

10492

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0109

AC:

734

AN:

67254

Other (OTH)

AF:

0.00668

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0106

Hom.:

Bravo

AF:

0.00643

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00958

AC:

1163

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00927

EpiControl

AF:

0.00936

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Benign:3

Dec 02, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not provided

Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGA: BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AGA-related disorder

Benign:1

Jun 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

2.0

PhyloP100

9.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.61

Sift

Benign

0.032

Sift4G

Uncertain

0.060

Polyphen

0.83

Vest4

0.65

MVP

0.96

MPC

0.53

ClinPred

0.040

GERP RS

5.9

PromoterAI

-0.0074

Neutral

(source)

Varity_R

0.70

gMVP

0.48

Mutation Taster

=73/27

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over