rs34241758

Positions:

• chr4-177440260-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264595.7(AGA):​c.281+13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,612,882 control chromosomes in the GnomAD database, including 37,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3066 hom., cov: 30)
  • Exomes 𝑓: 0.21 (34614 hom.)
• Consequence: AGA ENST00000264595.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0450

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-177440260-A-C is Benign according to our data. Variant chr4-177440260-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 92307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177440260-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGA	NM_000027.4	c.281+13T>G		intron_variant		ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.281+13T>G		intron_variant			NP_001165459.1
AGA	XM_047449722.1	c.281+13T>G		intron_variant			XP_047305678.1
AGA	NR_033655.2	n.343+13T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.281+13T>G		intron_variant		1	NM_000027.4	ENSP00000264595	P1
AGA	ENST00000511231.1	n.328T>G		non_coding_transcript_exon_variant	2/2	2
AGA	ENST00000506853.5	n.315+13T>G		intron_variant, non_coding_transcript_variant		2
AGA	ENST00000510955.5	n.315+13T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29095 AN: 151626 Hom.: 3069 Cov.: 30

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.194 AC: 48771 AN: 251390 Hom.: 5122 AF XY: 0.195 AC XY: 26444 AN XY: 135874

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.155

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.215 AC: 313426 AN: 1461138 Hom.: 34614 Cov.: 33 AF XY: 0.213 AC XY: 154644 AN XY: 726908

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.192 AC: 29088 AN: 151744 Hom.: 3066 Cov.: 30 AF XY: 0.190 AC XY: 14087 AN XY: 74110

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.234

Alfa AF: 0.215 Hom.: 906

Bravo AF: 0.187

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aspartylglucosaminuria Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.35
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34241758; hg19: chr4-178361414; COSMIC: COSV52806468; COSMIC: COSV52806468;