rs121964904

Variant names:

• chr4-177438764-C-G
• rs121964904
• NM_000027.4:c.488G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-177438764-C-G
• chr4-177438764-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM2 PP3 PP5_Very_Strong BP4

The NM_000027.4(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 NM_000027.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.62
• Publications: 29 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL, 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 VariationId is 219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AGA	NM_000027.4	c.488G>C	p.Cys163Ser	missense_variant	Exon 4 of 9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.488G>C	p.Cys163Ser	missense_variant	Exon 4 of 9		NP_001165459.1
AGA	XM_047449722.1	c.488G>C	p.Cys163Ser	missense_variant	Exon 4 of 7		XP_047305678.1
AGA	NR_033655.2	n.550G>C		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.488G>C	p.Cys163Ser	missense_variant	Exon 4 of 9	1	NM_000027.4	ENSP00000264595.2

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152150 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000784 AC: 197 AN: 251154 AF XY: 0.000766

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: 0.00813

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000328 AC: 475 AN: 1449900 Hom.: 0 Cov.: 29 AF XY: 0.000305 AC XY: 220 AN XY: 722188

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85998

European-Finnish (FIN) AF: 0.00779 AC: 416 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000291 AC: 32 AN: 1101036

Other (OTH) AF: 0.000450 AC: 27 AN: 60020

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00707 AC: 75 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000880 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000626 AC: 76

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:7

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

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. -

Dec 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 14, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 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 with a positive predictive value of 80%. 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. -

Dec 19, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aspartylglucosaminuria, finnish type Pathogenic:1

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.072	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		6.6
PrimateAI	Uncertain	0.60	T
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	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121964904; hg19: chr4-178359918;