4-177433252-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000027.4(AGA):c.902T>C(p.Phe301Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,614,130 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F301C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 8.65

Publications

2 publications found

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 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

AGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000027.4

BP4

Computational evidence support a benign effect (MetaRNN=0.021204501).

BP6

Variant 4-177433252-A-G is Benign according to our data. Variant chr4-177433252-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00336 (512/152362) while in subpopulation AFR AF = 0.0111 (461/41594). AF 95% confidence interval is 0.0102. There are 1 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AGA	NM_000027.4 link	c.902T>C	p.Phe301Ser	missense_variant	Exon 8 of 9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2 link	c.872T>C	p.Phe291Ser	missense_variant	Exon 8 of 9		NP_001165459.1
AGA	NR_033655.2 link	n.888T>C		non_coding_transcript_exon_variant	Exon 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7 link	c.902T>C	p.Phe301Ser	missense_variant	Exon 8 of 9	1	NM_000027.4	ENSP00000264595.2
AGA	ENST00000502310.5 link	c.*9T>C		downstream_gene_variant		5		ENSP00000423798.1

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

503

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00107

AC:

269

AN:

251432

AF XY:

0.000817

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000476

AC:

696

AN:

1461768

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0129

AC:

431

AN:

33476

American (AMR)

AF:

0.00101

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000121

AC:

134

AN:

1111968

Other (OTH)

AF:

0.00104

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00336

AC:

512

AN:

152362

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0111

AC:

461

AN:

41594

American (AMR)

AF:

0.00222

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.00368

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00120

AC:

146

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 15, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Jan 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aspartylglucosaminuria

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Dec 10, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.020

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.2

PhyloP100

8.7

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.38

Sift

Benign

0.66

Sift4G

Benign

0.59

Vest4

0.91

ClinPred

0.073

GERP RS

6.0

Varity_R

0.63

gMVP

0.96

Mutation Taster

=76/24

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over