4-177442332-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_000027.4(AGA):​c.44T>C​(p.Leu15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L15R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

AGA
NM_000027.4 missense

Scores

2
8
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83
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-DT (HGNC:27730): (AGA divergent transcript)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-177442332-A-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGANM_000027.4 linkc.44T>C p.Leu15Pro missense_variant Exon 1 of 9 ENST00000264595.7 NP_000018.2 P20933

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGAENST00000264595.7 linkc.44T>C p.Leu15Pro missense_variant Exon 1 of 9 1 NM_000027.4 ENSP00000264595.2 P20933

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461772
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
19
DANN
Benign
0.92
DEOGEN2
Uncertain
0.52
D
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.40
T
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.76
D
MetaSVM
Benign
-0.59
T
MutationAssessor
Uncertain
2.7
M
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.2
D
REVEL
Uncertain
0.37
Sift
Uncertain
0.010
D
Sift4G
Uncertain
0.014
D
Polyphen
0.011
B
Vest4
0.63
MutPred
0.63
Loss of stability (P = 0.0241);
MVP
0.67
MPC
0.59
ClinPred
0.77
D
GERP RS
1.9
Varity_R
0.52
gMVP
0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-178363486; API