chr4-177438525-T-C

Variant names:

• chr4-177438525-T-C
• rs2271100
• NM_000027.4:c.507+220A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000027.4(AGA):​c.507+220A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,132 control chromosomes in the GnomAD database, including 3,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3087 hom., cov: 32)
• Consequence: AGA NM_000027.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49
• Publications: 10 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: ClinGen, G2P, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-177438525-T-C is Benign according to our data. Variant chr4-177438525-T-C is described in ClinVar as Benign. ClinVar VariationId is 1238985.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	NM_000027.4	MANE Select	c.507+220A>G		intron	N/A	NP_000018.2
	AGA	NM_001171988.2		c.507+220A>G		intron	N/A	NP_001165459.1
	AGA	NR_033655.2		n.569+220A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	ENST00000264595.7	TSL:1 MANE Select	c.507+220A>G		intron	N/A	ENSP00000264595.2
	AGA	ENST00000510635.1	TSL:1	c.201+220A>G		intron	N/A	ENSP00000421471.1
	AGA	ENST00000926431.1		c.507+220A>G		intron	N/A	ENSP00000596490.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29181 AN: 152014 Hom.: 3090 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.237

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.192 AC: 29174 AN: 152132 Hom.: 3087 Cov.: 32 AF XY: 0.190 AC XY: 14158 AN XY: 74362

African (AFR) AF: 0.117 AC: 4876 AN: 41524

American (AMR) AF: 0.181 AC: 2762 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 824 AN: 3468

East Asian (EAS) AF: 0.149 AC: 770 AN: 5154

South Asian (SAS) AF: 0.116 AC: 557 AN: 4822

European-Finnish (FIN) AF: 0.240 AC: 2537 AN: 10584

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16049 AN: 67996

Other (OTH) AF: 0.234 AC: 494 AN: 2108

Alfa AF: 0.224 Hom.: 6733

Bravo AF: 0.187

Asia WGS AF: 0.148 AC: 516 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.54
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2271100; hg19: chr4-178359679;