rs2228119

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000027.4(AGA):c.446C>G(p.Thr149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,611,942 control chromosomes in the GnomAD database, including 787,480 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 67100 hom., cov: 33)

Exomes 𝑓: 0.99 ( 720380 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.231

Publications

32 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

AGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.053936E-7).

BP6

Variant 4-177438806-G-C is Benign according to our data. Variant chr4-177438806-G-C is described in ClinVar as Benign. ClinVar VariationId is 92308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGA	NM_000027.4	MANE Select	c.446C>G	p.Thr149Ser	missense	Exon 4 of 9	NP_000018.2	P20933
AGA	NM_001171988.2		c.446C>G	p.Thr149Ser	missense	Exon 4 of 9	NP_001165459.1
AGA	NR_033655.2		n.508C>G		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGA	ENST00000264595.7	TSL:1 MANE Select	c.446C>G	p.Thr149Ser	missense	Exon 4 of 9	ENSP00000264595.2	P20933
AGA	ENST00000510635.1	TSL:1	c.140C>G	p.Thr47Ser	missense	Exon 2 of 5	ENSP00000421471.1	H0Y8L9
AGA	ENST00000926431.1		c.446C>G	p.Thr149Ser	missense	Exon 4 of 9	ENSP00000596490.1

Frequencies

GnomAD3 genomes

AF:

0.933

AC:

141991

AN:

152148

Hom.:

67057

Cov.:

show subpopulations

Gnomad AFR

AF:

0.769

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.972

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.981

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.954

GnomAD2 exomes

AF:

0.982

AC:

246952

AN:

251388

AF XY:

0.987

show subpopulations

Gnomad AFR exome

AF:

0.763

Gnomad AMR exome

AF:

0.987

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.991

GnomAD4 exome

AF:

0.993

AC:

1449086

AN:

1459676

Hom.:

720380

Cov.:

AF XY:

0.994

AC XY:

721846

AN XY:

726342

show subpopulations

African (AFR)

AF:

0.751

AC:

25099

AN:

33408

American (AMR)

AF:

0.986

AC:

44072

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26114

AN:

26116

East Asian (EAS)

AF:

1.00

AC:

39688

AN:

39688

South Asian (SAS)

AF:

0.999

AC:

86157

AN:

86206

European-Finnish (FIN)

AF:

1.00

AC:

53416

AN:

53416

Middle Eastern (MID)

AF:

0.990

AC:

5706

AN:

5762

European-Non Finnish (NFE)

AF:

0.999

AC:

1109471

AN:

1110034

Other (OTH)

AF:

0.984

AC:

59363

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

456

913

1369

1826

2282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21604

43208

64812

86416

108020

<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:

0.933

AC:

142088

AN:

152266

Hom.:

67100

Cov.:

AF XY:

0.936

AC XY:

69667

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.769

AC:

31919

AN:

41494

American (AMR)

AF:

0.972

AC:

14864

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3471

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5190

AN:

5190

South Asian (SAS)

AF:

0.999

AC:

4819

AN:

4822

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67984

AN:

68046

Other (OTH)

AF:

0.954

AC:

2015

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

404

808

1212

1616

2020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.990

Hom.:

56412

Bravo

AF:

0.924

TwinsUK

AF:

0.999

AC:

3705

ALSPAC

AF:

0.999

AC:

3852

ESP6500AA

AF:

0.781

AC:

3443

ESP6500EA

AF:

0.999

AC:

8591

ExAC

AF:

0.978

AC:

118753

Asia WGS

AF:

0.984

AC:

3424

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aspartylglucosaminuria (7)

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.0020

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.33

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.010

MetaRNN

Benign

8.1e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.92

PhyloP100

-0.23

PrimateAI

Benign

0.26

PROVEAN

Benign

0.65

REVEL

Benign

0.20

Sift

Benign

0.73

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.019

MutPred

0.18

Gain of disorder (P = 0.0443)

MPC

0.094

ClinPred

0.00031

GERP RS

-4.7

Varity_R

0.019

gMVP

0.19

Mutation Taster

=97/3

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over