4-177439668-G-A

Position:

• chr4-177439668-G-A

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.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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 9.07

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 (HGNC:):

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 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/exons	MANE	Protein	UniProt
AGA	NM_000027.4	c.302C>T	p.Ala101Val	missense_variant	3/9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.302C>T	p.Ala101Val	missense_variant	3/9		NP_001165459.1
AGA	XM_047449722.1	c.302C>T	p.Ala101Val	missense_variant	3/7		XP_047305678.1
AGA	NR_033655.2	n.364C>T		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.302C>T	p.Ala101Val	missense_variant	3/9	1	NM_000027.4	ENSP00000264595.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251398 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

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: 7 AN: 1458834 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725796

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.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 15, 2016	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	Experimental studies have shown that this missense change affects AGA function (PMID: 10571008). For these reasons, this variant has been classified as Pathogenic. 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. 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). This variant is present in population databases (rs121964908, gnomAD 0.003%). 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. ClinVar contains an entry for this variant (Variation ID: 223). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 1991	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2021

- -

Autism Uncertain:1

Uncertain significance, no assertion criteria provided

research

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

-

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	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Gain of sheet (P = 0.1208);
MVP		0.99
MPC		0.53
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs121964908; hg19: chr4-178360822;