chr4-177440260-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000027.4(AGA):c.281+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,612,882 control chromosomes in the GnomAD database, including 37,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3066 hom., cov: 30)

Exomes 𝑓: 0.21 ( 34614 hom. )

Consequence

AGA
NM_000027.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0450

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 4-177440260-A-C is Benign according to our data. Variant chr4-177440260-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
AGA	NM_000027.4 link	c.281+13T>G	intron_variant	Intron 2 of 8	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2 link	c.281+13T>G	intron_variant	Intron 2 of 8		NP_001165459.1
AGA	NR_033655.2 link	n.343+13T>G	intron_variant	Intron 2 of 7
AGA	XM_047449722.1 link	c.281+13T>G	intron_variant	Intron 2 of 6		XP_047305678.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
AGA	ENST00000264595.7 link	c.281+13T>G	intron_variant	Intron 2 of 8	1	NM_000027.4	ENSP00000264595.2
AGA	ENST00000511231.1 link	n.328T>G	non_coding_transcript_exon_variant	Exon 2 of 2	2
AGA	ENST00000506853.5 link	n.315+13T>G	intron_variant	Intron 2 of 5	2
AGA	ENST00000510955.5 link	n.315+13T>G	intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29095

AN:

151626

Hom.:

3069

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.255

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.238

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.194

AC:

48771

AN:

251390

AF XY:

0.195

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.215

AC:

313426

AN:

1461138

Hom.:

34614

Cov.:

AF XY:

0.213

AC XY:

154644

AN XY:

726908

show subpopulations

African (AFR)

AF:

0.118

AC:

3965

AN:

33466

American (AMR)

AF:

0.155

AC:

6946

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

6079

AN:

26134

East Asian (EAS)

AF:

0.149

AC:

5909

AN:

39688

South Asian (SAS)

AF:

0.125

AC:

10806

AN:

86250

European-Finnish (FIN)

AF:

0.224

AC:

11933

AN:

53356

Middle Eastern (MID)

AF:

0.269

AC:

1553

AN:

5768

European-Non Finnish (NFE)

AF:

0.228

AC:

253127

AN:

1111386

Other (OTH)

AF:

0.217

AC:

13108

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

11898

23796

35694

47592

59490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8424

16848

25272

33696

42120

<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:

0.192

AC:

29088

AN:

151744

Hom.:

3066

Cov.:

AF XY:

0.190

AC XY:

14087

AN XY:

74110

show subpopulations

African (AFR)

AF:

0.117

AC:

4849

AN:

41370

American (AMR)

AF:

0.181

AC:

2756

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

823

AN:

3468

East Asian (EAS)

AF:

0.150

AC:

772

AN:

5146

South Asian (SAS)

AF:

0.116

AC:

560

AN:

4810

European-Finnish (FIN)

AF:

0.238

AC:

2503

AN:

10504

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.236

AC:

16028

AN:

67914

Other (OTH)

AF:

0.234

AC:

492

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1150

2301

3451

4602

5752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

310

620

930

1240

1550

<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:

0.211

Hom.:

1479

Bravo

AF:

0.187

Asia WGS

AF:

0.148

AC:

516

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:3

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.35

(source)

DANN

Benign

0.51

PhyloP100

-0.045

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over