rs386833426

Positions:

chr4-177438865-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000027.4(AGA):c.395-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000079 in 1,518,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000081 ( 0 hom. )

Consequence

AGA
NM_000027.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9984

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.935

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-177438865-T-C is Pathogenic according to our data. Variant chr4-177438865-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177438865-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
AGA	NM_000027.4 linkuse as main transcript	c.395-8A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000264595.7
AGA	NM_001171988.2 linkuse as main transcript	c.395-8A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
AGA	XM_047449722.1 linkuse as main transcript	c.395-8A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
AGA	NR_033655.2 linkuse as main transcript	n.457-8A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7 linkuse as main transcript	c.395-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000027.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250390

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

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:

0.00000805

AC:

AN:

1366186

Hom.:

Cov.:

AF XY:

0.00000730

AC XY:

AN XY:

685304

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000179

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000195

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2023	Variant summary: AGA c.395-8A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site, and three of four predict the variant also abolishes/weakens the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing by creating an alternative 3' acceptor site upstream from the canonical 3' acceptor site, resulting in a 7 bp insertion which ultimately leads to a frameshift and premature termination codon. The variant allele was found at a frequency of 8e-06 in 250390 control chromosomes (gnomAD). c.395-8A>G has been reported in the literature in the homozygous state in two siblings affected with Aspartylglucosaminuria (Yoshida_1992). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in an unstable protein with <10% of normal activity when expressed in vitro (Saarela_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11309371, 1427775). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 27, 2023	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Uncertain

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -1

DS_AL_spliceai

0.98

Position offset: -8

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