Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000027.4(AGA):c.503G>A(p.Trp168*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000422 in 1,421,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

AGA
NM_000027.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.62

Publications

2 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-177438749-C-T is Pathogenic according to our data. Variant chr4-177438749-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.503G>A	p.Trp168*	stop_gained	Exon 4 of 9	NP_000018.2
AGA	NM_001171988.2		c.503G>A	p.Trp168*	stop_gained	Exon 4 of 9	NP_001165459.1
AGA	NR_033655.2		n.565G>A		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGA	ENST00000264595.7	TSL:1 MANE Select	c.503G>A	p.Trp168*	stop_gained	Exon 4 of 9	ENSP00000264595.2
AGA	ENST00000510635.1	TSL:1	c.197G>A	p.Trp66*	stop_gained	Exon 2 of 5	ENSP00000421471.1
AGA	ENST00000502310.5	TSL:5	c.158G>A	p.Trp53*	stop_gained	Exon 2 of 5	ENSP00000423798.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

250860

AF XY:

0.0000221

show subpopulations

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000422

AC:

AN:

1421484

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32682

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

85396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00000558

AC:

AN:

1075144

Other (OTH)

AF:

0.00

AC:

AN:

59110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aspartylglucosaminuria (7)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.6

Vest4

0.98

ClinPred

0.99

GERP RS

5.6

Mutation Taster

=2/198

disease causing (ClinVar)

(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

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

rs386833430

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over