Genetic Variant AGA:p.Val12Leu (chr4-177442342-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000027.4(AGA):c.34G>T(p.Val12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,614,112 control chromosomes in the GnomAD database, including 415 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 27 hom., cov: 32)

Exomes 𝑓: 0.021 ( 388 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -1.74

Publications

5 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 links:

AGA-DT (HGNC:27730): (AGA divergent transcript)

AGA-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030047).

BP6

Variant 4-177442342-C-A is Benign according to our data. Variant chr4-177442342-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188964.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2282/152348) while in subpopulation NFE AF = 0.0232 (1580/68028). AF 95% confidence interval is 0.0223. There are 27 homozygotes in GnomAd4. There are 1030 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

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.34G>T	p.Val12Leu	missense	Exon 1 of 9	NP_000018.2	P20933
AGA	NM_001171988.2		c.34G>T	p.Val12Leu	missense	Exon 1 of 9	NP_001165459.1
AGA	NR_033655.2		n.96G>T		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGA	ENST00000264595.7	TSL:1 MANE Select	c.34G>T	p.Val12Leu	missense	Exon 1 of 9	ENSP00000264595.2	P20933
AGA	ENST00000926431.1		c.34G>T	p.Val12Leu	missense	Exon 1 of 9	ENSP00000596490.1
AGA	ENST00000506853.5	TSL:2	n.68G>T		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2283

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00403

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0144

AC:

3609

AN:

251166

AF XY:

0.0145

show subpopulations

Gnomad AFR exome

AF:

0.00481

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00481

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0208

AC:

30384

AN:

1461764

Hom.:

388

Cov.:

AF XY:

0.0205

AC XY:

14883

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00370

AC:

124

AN:

33476

American (AMR)

AF:

0.0127

AC:

567

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

547

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00428

AC:

369

AN:

86258

European-Finnish (FIN)

AF:

0.00537

AC:

287

AN:

53400

Middle Eastern (MID)

AF:

0.0251

AC:

145

AN:

5766

European-Non Finnish (NFE)

AF:

0.0244

AC:

27125

AN:

1111928

Other (OTH)

AF:

0.0202

AC:

1219

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1811

3621

5432

7242

9053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1018

2036

3054

4072

5090

<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:

0.0150

AC:

2282

AN:

152348

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1030

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00402

AC:

167

AN:

41586

American (AMR)

AF:

0.0177

AC:

271

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1580

AN:

68028

Other (OTH)

AF:

0.0237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0201

Hom.:

108

Bravo

AF:

0.0158

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0260

AC:

224

ExAC

AF:

0.0144

AC:

1753

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0274

EpiControl

AF:

0.0247

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aspartylglucosaminuria (5)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.20

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.087

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.71

PhyloP100

-1.7

PrimateAI

Benign

0.45

PROVEAN

Benign

0.17

REVEL

Benign

0.23

Sift

Benign

0.70

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.068

MutPred

0.79

Loss of sheet (P = 0.0011)

MPC

0.11

ClinPred

0.0061

GERP RS

-7.2

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.40

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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