rs386833432

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000027.4(AGA):c.754G>C(p.Gly252Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G252E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.51

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-177434433-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55952.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 4-177434434-C-G is Pathogenic according to our data. Variant chr4-177434434-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55951.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AGA	NM_000027.4 link	c.754G>C	p.Gly252Arg	missense_variant	Exon 7 of 9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2 link	c.724G>C	p.Gly242Arg	missense_variant	Exon 7 of 9		NP_001165459.1
AGA	NR_033655.2 link	n.740G>C		non_coding_transcript_exon_variant	Exon 6 of 8
AGA	XM_047449722.1 link	c.*48G>C		3_prime_UTR_variant	Exon 7 of 7		XP_047305678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGA	ENST00000264595.7 link	c.754G>C	p.Gly252Arg	missense_variant	Exon 7 of 9	1	NM_000027.4	ENSP00000264595.2
AGA	ENST00000502310.5 link	c.325G>C	p.Gly109Arg	missense_variant	Exon 4 of 5	5		ENSP00000423798.1
AGA	ENST00000506853.5 link	n.712G>C		non_coding_transcript_exon_variant	Exon 6 of 6	2
AGA	ENST00000510635.1 link	c.*6G>C		downstream_gene_variant		1		ENSP00000421471.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;.

PhyloP100

7.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;.

Vest4

0.99

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.99

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over