NM_000027.4:c.677G>A

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.677G>A(p.Gly226Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,612,820 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 (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.01

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 beta chain (size 140) in uniprot entity ASPG_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000027.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 4-177436297-C-T is Pathogenic according to our data. Variant chr4-177436297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177436297-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4 link	c.677G>A	p.Gly226Asp	missense_variant	Exon 6 of 9	ENST00000264595.7	NP_000018.2	P20933
AGA	NM_001171988.2 link	c.676+1G>A		splice_donor_variant, intron_variant	Intron 6 of 8		NP_001165459.1	P20933
AGA	XM_047449722.1 link	c.676+1G>A		splice_donor_variant, intron_variant	Intron 6 of 6		XP_047305678.1
AGA	NR_033655.2 link	n.684+1108G>A		intron_variant	Intron 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGA	ENST00000264595.7 link	c.677G>A	p.Gly226Asp	missense_variant	Exon 6 of 9	1	NM_000027.4	ENSP00000264595.2	P20933
AGA	ENST00000510635.1 link	c.370+1G>A		splice_donor_variant, intron_variant	Intron 4 of 4	1		ENSP00000421471.1	H0Y8L9
AGA	ENST00000502310.5 link	c.277+1108G>A		intron_variant	Intron 3 of 4	5		ENSP00000423798.1	H0Y9C7
AGA	ENST00000506853.5 link	n.656+1108G>A		intron_variant	Intron 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251294

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460902

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

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:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Pathogenic:5

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 226 of the AGA protein (p.Gly226Asp). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs386833431, gnomAD 0.002%). This missense change has been observed in individual(s) with AGA-related conditions (PMID: 10399108, 29930972). ClinVar contains an entry for this variant (Variation ID: 55950). 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: 11309371, 18992224). Studies have shown that this missense change results in skipping of exon 6 and introduces a new termination codon (PMID: 10399108, 11309371). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2019

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Sep 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect of significantly reduced enzyme activity (Sui et al., 2014; Saarela et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18992224, 25525159, 10399108, 11309371, 14616088, 28457719, 25456816) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.97

MutPred

0.98

Loss of methylation at K228 (P = 0.0598);

MVP

1.0

MPC

0.61

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.99

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