rs121964908

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000027.4(AGA):c.302C>T(p.Ala101Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,834 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A101A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 9.07

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Glycosylasparaginase alpha chain (size 181) in uniprot entity ASPG_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_000027.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 4-177439668-G-A is Pathogenic according to our data. Variant chr4-177439668-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177439668-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-177439668-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 9	ENST00000264595.7	NP_000018.2	P20933
AGA	NM_001171988.2 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 9		NP_001165459.1	P20933
AGA	XM_047449722.1 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 7		XP_047305678.1
AGA	NR_033655.2 link	n.364C>T		non_coding_transcript_exon_variant	Exon 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7 link	c.302C>T	p.Ala101Val	missense_variant	Exon 3 of 9	1	NM_000027.4	ENSP00000264595.2		P20933

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251398

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135866

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458834

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725796

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Pathogenic:6

Apr 15, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.302C>T (p.Ala101Val) missense variant in the AGA gene has been previously reported in two individuals affected with Aspartylglucosaminuria (Ikonen et al., 1991). In one of the affected individuals, this variant was observed in trans with a pathogenic variant (c.102_108del, p.Trp34*) (Ikonen et al., 1991). This variant is located at the dimer interface of the protein and is thus predicted to affect protein interaction and dimerization; additional, in vitro functional studies have shown the enzymatic activity was undetectable when this variant was introduced (Saito et al., 2008). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0%; 1000 Genomes = NA; and ExAC = 0.006%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.93; CADD = 36; PolyPhen = 1.0; SIFT = 0.0). AGA is the only gene in which pathogenic variants are known to cause Aspartylglucosaminuria. Therefore, this collective evidence supports the classification of the c.302C>T (p.Ala101Val) as a Likely pathogenic variant for Aspartylglucosaminuria. We have confirmed this finding in our laboratory using Sanger sequencing. -

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with clinical features of aspartylglucosaminuria (PMID: 1722323, 10571008). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AGA function (PMID: 10571008). 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. ClinVar contains an entry for this variant (Variation ID: 223). This variant is present in population databases (rs121964908, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 101 of the AGA protein (p.Ala101Val). -

Sep 06, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2020

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 15, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism

Uncertain:1

Centre for Addiction & Mental Health, Centre for Addiction & Mental Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Nonsynonymous variant in known disease gene; no homozygotes in gnomAD control data, but no functional assay data available -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.98

MutPred

0.96

Gain of sheet (P = 0.1208);

MVP

0.99

MPC

0.53

ClinPred

1.0

GERP RS

5.9

Varity_R

0.98

gMVP

0.93

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