rs2271101

Variant names:

• chr4-177438565-A-G
• rs2271101
• NM_000027.4:c.507+180T>C

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.507+180T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,966 control chromosomes in the GnomAD database, including 15,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.45 (15461 hom., cov: 32)
• Consequence: AGA NM_000027.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.891
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-177438565-A-G is Benign according to our data. Variant chr4-177438565-A-G is described in ClinVar as Benign. ClinVar VariationId is 1254787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4	c.507+180T>C		intron_variant	Intron 4 of 8	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.507+180T>C		intron_variant	Intron 4 of 8		NP_001165459.1
AGA	NR_033655.2	n.569+180T>C		intron_variant	Intron 4 of 7
AGA	XM_047449722.1	c.507+180T>C		intron_variant	Intron 4 of 6		XP_047305678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.507+180T>C		intron_variant	Intron 4 of 8	1	NM_000027.4	ENSP00000264595.2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68058 AN: 151848 Hom.: 15429 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.422

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

GnomAD4 genome AF: 0.448 AC: 68136 AN: 151966 Hom.: 15461 Cov.: 32 AF XY: 0.444 AC XY: 32958 AN XY: 74246

African (AFR) AF: 0.445 AC: 18453 AN: 41424

American (AMR) AF: 0.447 AC: 6825 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1536 AN: 5162

South Asian (SAS) AF: 0.317 AC: 1523 AN: 4812

European-Finnish (FIN) AF: 0.486 AC: 5126 AN: 10542

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31929 AN: 67972

Other (OTH) AF: 0.419 AC: 885 AN: 2114

Alfa AF: 0.459 Hom.: 8498

Bravo AF: 0.450

Asia WGS AF: 0.332 AC: 1157 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-0.89
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: rs2271101; hg19: chr4-178359719; COSMIC: COSV107277890; COSMIC: COSV107277890;