Genetic Variant AGA:c.*882A>C (chr4-177430826-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000027.4(AGA):c.*882A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 453,952 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 14 hom. )

Consequence

AGA
NM_000027.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.946

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-177430826-T-G is Benign according to our data. Variant chr4-177430826-T-G is described in ClinVar as [Benign]. Clinvar id is 902808.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00173 (263/152256) while in subpopulation EAS AF= 0.0469 (243/5176). AF 95% confidence interval is 0.0421. There are 9 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4 link	c.*882A>C	3_prime_UTR_variant	Exon 9 of 9	ENST00000264595.7	NP_000018.2	P20933
AGA	NM_001171988.2 link	c.*882A>C	3_prime_UTR_variant	Exon 9 of 9		NP_001165459.1	P20933
AGA	NR_033655.2 link	n.1909A>C	non_coding_transcript_exon_variant	Exon 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595 link	c.*882A>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_000027.4	ENSP00000264595.2		P20933

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

262

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.0466

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00469

AC:

611

AN:

130386

Hom.:

AF XY:

0.00437

AC XY:

311

AN XY:

71166

show subpopulations

Gnomad AFR exome

AF:

0.000657

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00247

Gnomad EAS exome

AF:

0.0529

Gnomad SAS exome

AF:

0.00116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000403

Gnomad OTH exome

AF:

0.00150

GnomAD4 exome

AF:

0.00202

AC:

608

AN:

301696

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

350

AN XY:

171926

show subpopulations

Gnomad4 AFR exome

AF:

0.000702

Gnomad4 AMR exome

AF:

0.0000367

Gnomad4 ASJ exome

AF:

0.00232

Gnomad4 EAS exome

AF:

0.0505

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000819

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00173

AC:

263

AN:

152256

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.0469

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000536

Hom.:

Bravo

AF:

0.00271

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.6

DANN

Benign

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over