rs34241758

Variant names:

• chr4-177440260-A-C
• rs34241758
• NM_000027.4:c.281+13T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000027.4(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 NM_000027.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0450
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• aspartylglucosaminuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	NM_000027.4	MANE Select	c.281+13T>G		intron	N/A	NP_000018.2	P20933
	AGA	NM_001171988.2		c.281+13T>G		intron	N/A	NP_001165459.1
	AGA	NR_033655.2		n.343+13T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	ENST00000264595.7	TSL:1 MANE Select	c.281+13T>G		intron	N/A	ENSP00000264595.2	P20933
	AGA	ENST00000926431.1		c.281+13T>G		intron	N/A	ENSP00000596490.1
	AGA	ENST00000511231.1	TSL:2	n.328T>G		non_coding_transcript_exon	Exon 2 of 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

GnomAD2 exomes AF: 0.194 AC: 48771 AN: 251390 AF XY: 0.195

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 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

African (AFR) AF: 0.118 AC: 3965 AN: 33466

American (AMR) AF: 0.155 AC: 6946 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 6079 AN: 26134

East Asian (EAS) AF: 0.149 AC: 5909 AN: 39688

South Asian (SAS) AF: 0.125 AC: 10806 AN: 86250

European-Finnish (FIN) AF: 0.224 AC: 11933 AN: 53356

Middle Eastern (MID) AF: 0.269 AC: 1553 AN: 5768

European-Non Finnish (NFE) AF: 0.228 AC: 253127 AN: 1111386

Other (OTH) AF: 0.217 AC: 13108 AN: 60368

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

African (AFR) AF: 0.117 AC: 4849 AN: 41370

American (AMR) AF: 0.181 AC: 2756 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3468

East Asian (EAS) AF: 0.150 AC: 772 AN: 5146

South Asian (SAS) AF: 0.116 AC: 560 AN: 4810

European-Finnish (FIN) AF: 0.238 AC: 2503 AN: 10504

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16028 AN: 67914

Other (OTH) AF: 0.234 AC: 492 AN: 2106

Alfa AF: 0.211 Hom.: 1479

Bravo AF: 0.187

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Aspartylglucosaminuria (5)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.35
DANN	Benign	0.51
PhyloP100		-0.045
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34241758; hg19: chr4-178361414; COSMIC: COSV52806468; COSMIC: COSV52806468;