4-177431612-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000027.4(AGA):c.*96A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,021,006 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: AGA NM_000027.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.63

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGA	NM_000027.4	c.*96A>T		3_prime_UTR_variant	9/9	ENST00000264595.7
AGA	NM_001171988.2	c.*96A>T		3_prime_UTR_variant	9/9
AGA	NR_033655.2	n.1123A>T		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7	c.*96A>T		3_prime_UTR_variant	9/9	1	NM_000027.4	P1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000937 AC: 163 AN: 174012 Hom.: 1 AF XY: 0.000871 AC XY: 81 AN XY: 92968

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.000870 AC: 756 AN: 868672 Hom.: 1 Cov.: 12 AF XY: 0.000906 AC XY: 408 AN XY: 450292

Gnomad4 AFR exome AF: 0.000142

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000626

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74498

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000646 Hom.: 0

Bravo AF: 0.000929

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aspartylglucosaminuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.19
Dann	Benign	0.67

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: rs141424240; hg19: chr4-178352766;