4-177438806-G-C

Position:

• chr4-177438806-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 15/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.231

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain Glycosylasparaginase alpha chain (size 181) in uniprot entity ASPG_HUMAN there are 23 pathogenic changes around while only 9 benign (72%) in NM_000027.4
• 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 id is 92308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177438806-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGA	NM_000027.4	c.446C>G	p.Thr149Ser	missense_variant	4/9	ENST00000264595.7
AGA	NM_001171988.2	c.446C>G	p.Thr149Ser	missense_variant	4/9
AGA	XM_047449722.1	c.446C>G	p.Thr149Ser	missense_variant	4/7
AGA	NR_033655.2	n.508C>G		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7	c.446C>G	p.Thr149Ser	missense_variant	4/9	1	NM_000027.4	P1

Frequencies

GnomAD3 genomes AF: 0.933 AC: 141991 AN: 152148 Hom.: 67057 Cov.: 33

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

GnomAD3 exomes AF: 0.982 AC: 246952 AN: 251388 Hom.: 121720 AF XY: 0.987 AC XY: 134133 AN XY: 135884

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 SAS 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.: 46 AF XY: 0.994 AC XY: 721846 AN XY: 726342

Gnomad4 AFR exome AF: 0.751

Gnomad4 AMR exome AF: 0.986

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.984

GnomAD4 genome AF: 0.933 AC: 142088 AN: 152266 Hom.: 67100 Cov.: 33 AF XY: 0.936 AC XY: 69667 AN XY: 74460

Gnomad4 AFR AF: 0.769

Gnomad4 AMR AF: 0.972

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.954

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

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aspartylglucosaminuria Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2012	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.0020
DANN	Benign	0.34
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.010	T;T
MetaRNN	Benign	8.1e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.92	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.65	N;N
REVEL	Benign	0.20
Sift	Benign	0.73	T;T
Sift4G	Benign	0.70	T;.
Polyphen		0.0	B;.
Vest4		0.019
MutPred		0.18		Gain of disorder (P = 0.0443);.;
MPC		0.094
ClinPred		0.00031	T
GERP RS		-4.7
Varity_R		0.019
gMVP		0.19

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

Other links and lift over

dbSNP: rs2228119; hg19: chr4-178359960;