rs121964908

Variant names:

• chr4-177439668-G-A
• rs121964908
• NM_000027.4:c.302C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 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 (★★). ClinVar reports functional evidence for this variant: "SCV000494233: additional, in vitro functional studies have shown the enzymatic activity was undetectable when this variant was introduced (Saito et al., 2008)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101T) has been classified as Likely pathogenic.

• 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:8 U:1
• Conservation: PhyloP100: 9.07
• Publications: 4 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000494233: additional, in vitro functional studies have shown the enzymatic activity was undetectable when this variant was introduced (Saito et al., 2008).; SCV002228052: Experimental studies have shown that this missense change affects AGA function (PMID: 10571008).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-177439669-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1495375.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	NM_000027.4	MANE Select	c.302C>T	p.Ala101Val	missense	Exon 3 of 9	NP_000018.2	P20933
	AGA	NM_001171988.2		c.302C>T	p.Ala101Val	missense	Exon 3 of 9	NP_001165459.1
	AGA	NR_033655.2		n.364C>T		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	ENST00000264595.7	TSL:1 MANE Select	c.302C>T	p.Ala101Val	missense	Exon 3 of 9	ENSP00000264595.2	P20933
	AGA	ENST00000926431.1		c.302C>T	p.Ala101Val	missense	Exon 3 of 9	ENSP00000596490.1
	AGA	ENST00000506853.5	TSL:2	n.336C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251398 AF XY: 0.00000736

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: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109698

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000159 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Aspartylglucosaminuria (7)
-	1	-	Autism (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.1
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
PromoterAI		-0.021	Neutral
Varity_R		0.98
gMVP		0.93
Mutation Taster		=2/98	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: rs121964908; hg19: chr4-178360822;