rs386833429

Positions:

• chr4-177442332-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000027.4(AGA):​c.44T>G​(p.Leu15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,772 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.83

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 4-177442332-A-C is Pathogenic according to our data. Variant chr4-177442332-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55948.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-177442332-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGA	NM_000027.4	c.44T>G	p.Leu15Arg	missense_variant	1/9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.44T>G	p.Leu15Arg	missense_variant	1/9		NP_001165459.1
AGA	XM_047449722.1	c.44T>G	p.Leu15Arg	missense_variant	1/7		XP_047305678.1
AGA	NR_033655.2	n.106T>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.44T>G	p.Leu15Arg	missense_variant	1/9	1	NM_000027.4	ENSP00000264595	P1
AGA	ENST00000506853.5	n.78T>G		non_coding_transcript_exon_variant	1/6	2
AGA	ENST00000510955.5	n.78T>G		non_coding_transcript_exon_variant	1/4	2
AGA	ENST00000511231.1	n.78T>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461772 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.022	D
Polyphen		0.73	P
Vest4		0.73
MutPred		0.92		Gain of methylation at L15 (P = 0.0293);
MVP		0.86
MPC		0.46
ClinPred		0.94	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.74

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: rs386833429; hg19: chr4-178363486;