4-177442342-C-A

Position:

chr4-177442342-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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:5

Conservation

PhyloP100: -1.74

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AGA	NM_000027.4 linkuse as main transcript	c.34G>T	p.Val12Leu	missense_variant	1/9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2 linkuse as main transcript	c.34G>T	p.Val12Leu	missense_variant	1/9		NP_001165459.1
AGA	XM_047449722.1 linkuse as main transcript	c.34G>T	p.Val12Leu	missense_variant	1/7		XP_047305678.1
AGA	NR_033655.2 linkuse as main transcript	n.96G>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AGA	ENST00000264595.7 linkuse as main transcript	c.34G>T	p.Val12Leu	missense_variant	1/9	1	NM_000027.4	ENSP00000264595	P1
AGA	ENST00000506853.5 linkuse as main transcript	n.68G>T		non_coding_transcript_exon_variant	1/6	2
AGA	ENST00000510955.5 linkuse as main transcript	n.68G>T		non_coding_transcript_exon_variant	1/4	2
AGA	ENST00000511231.1 linkuse as main transcript	n.68G>T		non_coding_transcript_exon_variant	1/2	2

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

GnomAD3 exomes

AF:

0.0144

AC:

3609

AN:

251166

Hom.:

AF XY:

0.0145

AC XY:

1971

AN XY:

135860

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 SAS exome

AF:

0.00402

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

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0209

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00428

Gnomad4 FIN exome

AF:

0.00537

Gnomad4 NFE exome

AF:

0.0244

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0150

AC:

2282

AN:

152348

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1030

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00402

Gnomad4 AMR

AF:

0.0177

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.0232

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0206

Hom.:

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	literature only	Counsyl	Sep 19, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	This variant is associated with the following publications: (PMID: 11309371) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.20

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

MutationTaster

Benign

1.0

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over