rs2228119

Positions:

• chr4-177438806-G-A
• chr4-177438806-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000027.4(AGA):​c.446C>T​(p.Thr149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T149S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09750086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGA	NM_000027.4	c.446C>T	p.Thr149Ile	missense_variant	4/9	ENST00000264595.7
AGA	NM_001171988.2	c.446C>T	p.Thr149Ile	missense_variant	4/9
AGA	XM_047449722.1	c.446C>T	p.Thr149Ile	missense_variant	4/7
AGA	NR_033655.2	n.508C>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGA	ENST00000264595.7	c.446C>T	p.Thr149Ile	missense_variant	4/9	1	NM_000027.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.026
DANN	Benign	0.95
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.15	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T
Sift4G	Benign	0.14	T;.
Polyphen		0.0	B;.
Vest4		0.049
MutPred		0.40		Loss of disorder (P = 0.0272);.;
MVP		0.61
MPC		0.11
ClinPred		0.14	T
GERP RS		-4.7
Varity_R		0.035
gMVP		0.24

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;