4-177430793-C-G

Variant names:

• chr4-177430793-C-G
• rs745380599
• NM_000027.4:c.*915G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000027.4(AGA):​c.*915G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 301,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: AGA NM_000027.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

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.*915G>C		3_prime_UTR	Exon 9 of 9	NP_000018.2	P20933
	AGA	NM_001171988.2		c.*915G>C		3_prime_UTR	Exon 9 of 9	NP_001165459.1
	AGA	NR_033655.2		n.1942G>C		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGA	ENST00000264595.7	TSL:1 MANE Select	c.*915G>C		3_prime_UTR	Exon 9 of 9	ENSP00000264595.2	P20933

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000768 AC: 1 AN: 130278 AF XY: 0.0000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000332 AC: 1 AN: 301080 Hom.: 0 Cov.: 0 AF XY: 0.00000583 AC XY: 1 AN XY: 171510

African (AFR) AF: 0.00 AC: 0 AN: 8510

American (AMR) AF: 0.00 AC: 0 AN: 27236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10768

East Asian (EAS) AF: 0.00 AC: 0 AN: 9202

South Asian (SAS) AF: 0.0000168 AC: 1 AN: 59612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158224

Other (OTH) AF: 0.00 AC: 0 AN: 14018

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.16
DANN	Benign	0.58
PhyloP100		-0.20

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: rs745380599; hg19: chr4-178351947;