rs121964904

Positions:

chr4-177438764-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM2PP3PP5_Very_StrongBP4

The ENST00000264595.7(AGA):c.488G>C(p.Cys163Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000346 in 1,602,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C163C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

AGA
ENST00000264595.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.62

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Glycosylasparaginase alpha chain (size 181) in uniprot entity ASPG_HUMAN there are 23 pathogenic changes around while only 9 benign (72%) in ENST00000264595.7

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 4-177438764-C-G is Pathogenic according to our data. Variant chr4-177438764-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177438764-C-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.072190255). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AGA	NM_000027.4 linkuse as main transcript	c.488G>C	p.Cys163Ser	missense_variant	4/9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2 linkuse as main transcript	c.488G>C	p.Cys163Ser	missense_variant	4/9		NP_001165459.1
AGA	XM_047449722.1 linkuse as main transcript	c.488G>C	p.Cys163Ser	missense_variant	4/7		XP_047305678.1
AGA	NR_033655.2 linkuse as main transcript	n.550G>C		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7 linkuse as main transcript	c.488G>C	p.Cys163Ser	missense_variant	4/9	1	NM_000027.4	ENSP00000264595	P1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00707

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000784

AC:

197

AN:

251154

Hom.:

AF XY:

0.000766

AC XY:

104

AN XY:

135790

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00813

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000328

AC:

475

AN:

1449900

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

220

AN XY:

722188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00779

Gnomad4 NFE exome

AF:

0.0000291

Gnomad4 OTH exome

AF:

0.000450

GnomAD4 genome

AF:

0.000525

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00707

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000880

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000626

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_000027.3(AGA):c.488G>C(C163S) is classified as pathogenic in the context of aspartylglucosaminuria. Sources cited for classification include the following: PMID 11309371, 1904874, 1559710, 1765378 and 9742145. Classification of NM_000027.3(AGA):c.488G>C(C163S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000027.3:c.488G>C in the AGA gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The c.488G>C (p.Cys163Ser) variant has been reported previously in the compound heterozygous states (C163S/R161Q) in association with aspartylglucosaminuria (PMID: 1904874; 7627186; 2011603). In vitro functional studies demonstrated that p.Cys163Ser results in deficient enzyme activity (PMID: 1904874; 1765378). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3; PS3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2020	Variant summary: AGA c.488G>C (p.Cys163Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251288 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488G>C has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Aspartylglucosaminuria (Fisher_1991, Ikonen_1991, Tollersrud_1994, Saarela_2001). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant impaired processing of the precursor molecule into subunits and reduced AGA activity (Fish_1991, Riikonen_1994, Banning_2016). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2023	This variant is also known as AGAFin. ClinVar contains an entry for this variant (Variation ID: 219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGA protein function. Experimental studies have shown that this missense change affects AGA function (PMID: 1765378, 1904874, 8172656). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 1703489, 1904874, 2011603, 7627186, 11309371, 21228398). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 163 of the AGA protein (p.Cys163Ser). This variant is present in population databases (rs121964904, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. -

Aspartylglucosaminuria, finnish type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.072

T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-9.3

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0030

D;.

Polyphen

1.0

D;.

Vest4

0.92

MutPred

0.82

Gain of disorder (P = 0.0227);.;

MVP

0.99

MPC

0.59

ClinPred

0.97

GERP RS

5.7

Varity_R

0.96

gMVP

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over