rs121964909

chr4-177440340-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000027.4(AGA):c.214T>C(p.Ser72Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S72S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.15

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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 NM_000027.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 4-177440340-A-G is Pathogenic according to our data. Variant chr4-177440340-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177440340-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGA	NM_000027.4	c.214T>C	p.Ser72Pro	missense_variant	2/9	ENST00000264595.7
AGA	NM_001171988.2	c.214T>C	p.Ser72Pro	missense_variant	2/9
AGA	XM_047449722.1	c.214T>C	p.Ser72Pro	missense_variant	2/7
AGA	NR_033655.2	n.276T>C		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7	c.214T>C	p.Ser72Pro	missense_variant	2/9	1	NM_000027.4	P1
AGA	ENST00000506853.5	n.248T>C		non_coding_transcript_exon_variant	2/6	2
AGA	ENST00000510955.5	n.248T>C		non_coding_transcript_exon_variant	2/4	2
AGA	ENST00000511231.1	n.248T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2023	Variant summary: AGA c.214T>C (p.Ser72Pro) 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 was absent in 251482 control chromosomes (gnomAD). c.214T>C has been reported in the literature in both homozygous and compound heterozygous individuals affected with Aspartylglucosaminuria (e.g., Peltola_1996, Banning_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant leads to abnormal intracellular processing, which leads to reduced AGA activity relative to the wild-type (e.g., Peltola_1996). The following publications have been ascertained in the context of this evaluation (PMID: 29247835, 8776587). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 28, 2023	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 72 of the AGA protein (p.Ser72Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 8776587). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 229). 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: 8776587). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	0.073
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	0.92	A
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.92	P
Vest4		0.87
MutPred		0.81		Gain of glycosylation at S72 (P = 0.0704);
MVP		0.94
MPC		0.50
ClinPred		0.99	D
GERP RS		-0.29
Varity_R		0.94
gMVP		0.90

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

Other links and lift over

dbSNP: rs121964909; hg19: chr4-178361494;