NM_000027.4:c.902T>G

Variant names:

• chr4-177433252-A-C
• rs35916166
• NM_000027.4:c.902T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000027.4(AGA):​c.902T>G​(p.Phe301Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F301S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AGA NM_000027.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.65
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• aspartylglucosaminuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000027.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	NM_000027.4	MANE Select	c.902T>G	p.Phe301Cys	missense	Exon 8 of 9	NP_000018.2	P20933
	AGA	NM_001171988.2		c.872T>G	p.Phe291Cys	missense	Exon 8 of 9	NP_001165459.1
	AGA	NR_033655.2		n.888T>G		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	ENST00000264595.7	TSL:1 MANE Select	c.902T>G	p.Phe301Cys	missense	Exon 8 of 9	ENSP00000264595.2	P20933
	AGA	ENST00000926431.1		c.917T>G	p.Phe306Cys	missense	Exon 8 of 9	ENSP00000596490.1
	AGA	ENST00000502310.5	TSL:5	c.*9T>G		downstream_gene	N/A	ENSP00000423798.1	H0Y9C7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251432 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Aspartylglucosaminuria (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.83
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.96	D
Vest4		0.91
MVP		0.97
MPC		0.55
ClinPred		0.72	D
GERP RS		6.0
Varity_R		0.80
gMVP		0.97
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs35916166; hg19: chr4-178354406;