4-177439657-G-T

Position:

chr4-177439657-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000027.4(AGA):c.313C>A(p.Leu105Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,610,468 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 13 hom., cov: 33)

Exomes 𝑓: 0.010 ( 111 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 9.07

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000027.4

BP4

Computational evidence support a benign effect (MetaRNN=0.012048036).

BP6

Variant 4-177439657-G-T is Benign according to our data. Variant chr4-177439657-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 529230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177439657-G-T is described in Lovd as [Likely_benign]. Variant chr4-177439657-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00854 (1290/150996) while in subpopulation NFE AF= 0.0109 (734/67254). AF 95% confidence interval is 0.0103. There are 13 homozygotes in gnomad4. There are 718 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AGA	NM_000027.4 linkuse as main transcript	c.313C>A	p.Leu105Ile	missense_variant	3/9	ENST00000264595.7
AGA	NM_001171988.2 linkuse as main transcript	c.313C>A	p.Leu105Ile	missense_variant	3/9
AGA	XM_047449722.1 linkuse as main transcript	c.313C>A	p.Leu105Ile	missense_variant	3/7
AGA	NR_033655.2 linkuse as main transcript	n.375C>A		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7 linkuse as main transcript	c.313C>A	p.Leu105Ile	missense_variant	3/9	1	NM_000027.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00855

AC:

1290

AN:

150878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00177

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.00179

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00675

GnomAD3 exomes

AF:

0.00981

AC:

2467

AN:

251432

Hom.:

AF XY:

0.00972

AC XY:

1321

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.0193

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.0298

Gnomad NFE exome

AF:

0.0129

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0104

AC:

15123

AN:

1459472

Hom.:

111

Cov.:

AF XY:

0.00997

AC XY:

7237

AN XY:

726122

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.0198

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.0283

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00705

GnomAD4 genome

AF:

0.00854

AC:

1290

AN:

150996

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

718

AN XY:

73858

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00179

Gnomad4 ASJ

AF:

0.0230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0310

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.00668

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00643

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00958

AC:

1163

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00927

EpiControl

AF:

0.00936

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

AGA-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

AGA: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.61

Sift

Benign

0.032

Sift4G

Uncertain

0.060

Polyphen

0.83

Vest4

0.65

MVP

0.96

MPC

0.53

ClinPred

0.040

GERP RS

5.9

Varity_R

0.70

gMVP

0.48

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

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