Variant chr4-177438813-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000027.4(AGA):c.439T>A(p.Ser147Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S147P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

AGA
NM_000027.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.39

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:

AGA (HGNC:):

AGA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a chain Glycosylasparaginase alpha chain (size 181) in uniprot entity ASPG_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_000027.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-177438813-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.30071777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGA	NM_000027.4 linkuse as main transcript	c.439T>A	p.Ser147Thr	missense_variant	4/9	ENST00000264595.7	NP_000018.2	P20933
AGA	NM_001171988.2 linkuse as main transcript	c.439T>A	p.Ser147Thr	missense_variant	4/9		NP_001165459.1	P20933
AGA	XM_047449722.1 linkuse as main transcript	c.439T>A	p.Ser147Thr	missense_variant	4/7		XP_047305678.1
AGA	NR_033655.2 linkuse as main transcript	n.501T>A		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7 linkuse as main transcript	c.439T>A	p.Ser147Thr	missense_variant	4/9	1	NM_000027.4	ENSP00000264595.2		P20933

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.26

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

0.0078

Eigen_PC

Benign

0.066

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

N;.

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.21

Sift

Benign

0.58

T;T

Sift4G

Benign

0.88

T;.

Polyphen

0.0030

B;.

Vest4

0.070

MutPred

0.40

Loss of disorder (P = 0.0764);.;

MVP

0.91

MPC

0.097

ClinPred

0.81

GERP RS

4.4

Varity_R

0.18

gMVP

0.49

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over